Lisinopril compositions with an ingestible event marker

ABSTRACT

Provided herein are compositions for the ingestible administration of lisinopril. In some embodiments the compositions comprise lisinopril and silicon. In some embodiments, the compositions comprise lisinopril, silicon, magnesium metal, and copper (I) chloride. Also provided herein are apparatuses comprising the compositions provided herein. Also provided herein are methods for using the compositions and apparatuses provided herein.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/490,010, filed Apr. 25, 2017, the entire content of which isincorporated herein by reference.

INTRODUCTION

Prescription medications are effective remedies for many patients whentaken as instructed by the prescribing physician. However, studies haveshown that, on average, about 50% of patients do not comply withprescribed medication regimens. A low rate of compliance with medicationregimens results in a large number of hospitalizations and admissions tonursing homes every year. In the United States alone, it has recentlybeen estimated that the cost resulting from patient non-compliance isreaching $100 billion annually.

One example situation where patient adherence is of particularimportance is in the context of clinical studies. Non-adherence in theclinical trial setting has long-range consequences far beyond the fewhundred patients who might be involved in a trial. To the extent thatnon-adherence occurs without a correction factor, it may have effectsranging from failure to gain Food and Drug Administration (FDA) approvalto the necessity for increasing the recommended dose beyond that whichwould be required of a fully compliant population. Such an elevated dosecould cause a higher incidence of side effects, which in turn may leadto further non-adherence.

Clinical studies typically enroll patients to undergo specific drugtreatment regimens with the goal of testing hypotheses related to theeffects of drug treatment on medically relevant clinical endpoints. Suchstudies might measure, for example, the relationship between alternativedrug treatments with any of a wide variety of clinical endpoints,ranging from physiological, biochemical or psychological measurements,to manifestations of disease, patient survival or quality of life. Inaddition, drug treatments must also be related to any observed adverseevents in an effort to identify rare adverse reactions or interactionswith other medications.

The ability to reliably correlate highly specific drug treatmentregimens, including dosage and administration methods, with bothefficacy and safety depends to a great extent on the certainty ofknowledge that every patient has followed the prescribed treatmentregimen. Monitoring of patient adherence, including the exact time ofadministration for medications, is therefore of great value to patientsand their physicians, as well as clinical trial sponsors and thepharmaceutical industry in general.

Various methods and apparatuses have been made available to improvepatient compliance with prescribed regimens in efforts to improvepatient health. Transdermal delivery systems combined with a uniquebiologically active ingredient provide sustained release formulationsfor the safe and efficacious transdermal administration of the uniquebiologically active ingredient to a subject through a body surface ormembrane over a sustained time period for the treatment of variousdiseases. The transdermal route of parenteral delivery of drugs andother biologically active ingredients (“agents”) has been proposed for awide variety of systemically acting and locally acting agents on eithera rate-controlled or non-rate-controlled basis. For example, sustainedrelease formulations for the safe and efficacious administration ofpharmaceutical active ingredients for the treatment of hypertension,congestive heart failure, and acute and chronic renal failure, amongother things, have been proposed.

Additionally, different types of “smart” packaging devices have beendeveloped. In some cases, such devices automatically dispense theappropriate pill. In other cases, there are electronic controls thatdetect and record when the pill is taken out of the box. However,improvements of patient compliance with prescription regimens have notaddressed automatic tracking of oral administration (e.g., ingestion) oflisinopril (a.k.a.,(2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylicacid, PRINIVIL®, ZESTRIL®) to a patient in need of administrationthereof.

Thus, provided herein are methods of oral administration of lisinoprilwith an electronic circuitry system such as the electronic circuitrysystem developed by Proteus Digital Health, Inc. described in U.S. Pat.Nos. 7,978,064; 8,674,825; 8,730,031; 8,802,183; 8,816,847; 8,836,513;8,847,766; and 8,912,908, the disclosures of which are incorporated intheir entirety herein by reference. Also provided herein are deliverysystems employing electronic circuits combined with specificformulations of lisinopril to provide different techniques for trackingoral delivery of the lisinopril to a patient in need of administrationof lisinopril.

The present disclosure provides a unique composition of mattercomprising the combination of the electronic circuitry comprisingbattery forming materials and specific formulations of lisinopril toconfirm the delivery of the specific formulations of lisinopril. Thepresent novel composition of matter also overcomes the unpredictablenature of combining various metals and salts with the specificformulations of lisinopril to provide an electronic delivery system thatgenerates its own electrical power from a partial energy sourcecomprised of dissimilar materials when exposed with the bodily fluids ofa patient during the oral administration of the specific formulations oflisinopril.

The present disclosure relates generally to a composition of matter forthe active monitoring of the ingestible administration of lisinopril.The composition of matter includes lisinopril, magnesium metal andcopper chloride (e.g., copper (I) chloride, CuCl, or cuprous chloride).These materials and the final complete tablet formulation were chosenfor a variety of reasons. First, we were able to show that this specificformulation of copper chloride, magnesium metal, connected by siliconthat is conductive when wet, do not appreciably alter the chemicalcomposition of lisinopril when ingested even after being stored aftermanufacturing for an extended period of time. Second, the combination oflisinopril with copper chloride, magnesium metal and silicon does notfacilitate the reaction of copper chloride and magnesium metal. Such areaction, for example while being stored after manufacturing and beforedelivery to a patient, could cause the magnesium metal or copperchloride to react; the bi-products of such a reaction could change thechemical composition of the lisinopril; or, if all or most of themagnesium metal or copper chloride are reacted, render the ingestionsensor powerless and inert when ingested. Thus, uniquely, a formulationcontaining the lisinopril and the materials that make up the ingestionsensor must be found and proven to not adversely affect the purpose ofthe other.

An example of how this conflict has manifested itself in earlyexperiments demonstrates this unique challenge: early experiments weremade without any lisinopril in the tablet—just the ingestion sensor and“placebo” formulation of inert materials. A placebo pill without anembedded ingestion sensor can sit in an open container in a hot, humidbathroom for months without changing its ultimate performance. Many—butnot all—pharmaceuticals or dietary supplements such as vitamins can bestored in a similar manner without adversely affecting theireffectiveness. When in our early experiments we added ingestion sensorsto such “placebo” tablets, however, we found that the partial powersource made of copper chloride (e.g., copper (I) chloride, CuCl, orcuprous chloride) and magnesium metal would react with eachother—effectively “discharging” the biogalvanic potential—before theplacebo-with-ingestion-sensor tablet was ingested. Further, with someactive ingredients, the relaxation of polymer skirt size could cause thetablet to break up into pieces. Thus, the process of discovering andvalidating a precise formulation including lisinopril, magnesium metal,copper chloride and silicon that allows all of these materials to stablyco-exist for an extended period of time is a unique challenge thatdepends upon the reactivity of the lisinopril as formulated with thepair of electrochemically active materials, magnesium metal and copperchloride. More specifically, the present disclosure relates tocompositions used in an apparatus for automatic (i.e. electronic)identification of ingestion, i.e., oral administration, of lisinopril.

SUMMARY

According to one aspect of the present disclosure, a composition ofmatter for the ingestible administration of lisinopril is provided. Insome embodiments, the composition comprises lisinopril, magnesium metal,copper chloride, and silicon. In some embodiments, the compositioncomprises lisinopril; and silicon having a mass equivalent to a siliconsubstrate having dimensions of between 0.5×0.5×0.5 mm (0.125 mm³) and3×3×1 mm (09 mm³), or more particularly, roughly 1.0×1.0×0.3 mm (0.3mm³).

According to one aspect of the present disclosure, an apparatus isprovided. The apparatus comprises lisinopril; a substrate with a firstsurface and a second surface; a partial power source comprising a firstmaterial provided on the first surface of the substrate, wherein thefirst material is magnesium metal, and a second material provided on thesecond surface of the substrate, wherein the second material is copperchloride (e.g., copper (I) chloride, CuCl, or cuprous chloride), whereinthe partial power source is configured to generate power upon contact ofthe first material and the second material with a fluid; and a controlunit electronically coupled with the partial power source, wherein thecontrol unit is configured to be activated by receiving the power fromthe partial power source and to encode information in a current flowthrough the fluid.

BRIEF DESCRIPTION OF THE FIGURES

The features of the various aspects of the present disclosure are setforth with particularity in the appended claims. The various aspects,both as to organization and methods of operation, together withadvantages thereof, may, however best be understood by reference to thefollowing description, taken in conjunction with the accompanyingdrawings as follows:

FIG. 1 is a diagrammatic, exemplary representation of the pillembodiment of the present disclosure, according to one aspect of thepresent disclosure.

FIG. 2 is a more detailed view of the pill composition shown in FIG. 1 ,according to one aspect of the present disclosure.

FIG. 3 is an example embodiment of signal generation elements of thepill composition shown in FIG. 1 , according to one aspect of thepresent disclosure.

FIGS. 4A and 4B are example embodiments of signal generation elements ofthe pill composition shown in FIG. 1 , according to some aspects of thepresent disclosures.

FIG. 5 is an assembling apparatus for assembling a signal generationelement on a tablet, according to one aspect of the present disclosure.

FIG. 6 is a close-up view of a portion of a portion of the apparatus ofFIG. 5 with specific indication of the direction of force applied,according to one aspect of the present disclosure.

FIG. 7 is a close-up view of a portion of a feeder assembly of theapparatus of FIG. 5 , according to one aspect of the present disclosure.

FIG. 8 is a close-up view of a portion of a feeder assembly that can beused with the apparatus of FIG. 5 in accordance with another aspect ofthe present disclosure.

FIG. 9A is a close-up view of a portion of a feeder assembly that can beused with the apparatus of FIG. 5 in accordance with another aspect ofthe present disclosure.

FIG. 9B is a close-up view of a portion of the feeder assembly shown inFIG. 9A at an advanced stage in the loading process, according to oneaspect of the present disclosure.

FIG. 10 shows the change in time to activation over 6 months of aningestible event marker in certain of the SP-TAB lisinopril compositionsprovided herein.

FIG. 11 shows the change in die fall-out percentage over six months ofan ingestible event marker in certain of the SP-TAB lisinoprilcompositions provided herein.

FIG. 12 shows the change in time to activation over 6 months of aningestible event marker in certain of the IEM-TAB lisinoprilcompositions provided herein; “2560” corresponds to 25° C./60% relativehumidity (RH), and “4075” corresponds to 40° C./75% RH.

FIG. 13 shows the change in die fall-out percentage over six months ofan ingestible event marker in certain of the IEM-TAB lisinoprilcompositions provided herein; “2560” corresponds to 25° C./60% relativehumidity (RH), and “4075” corresponds to 40° C./75% RH.

DETAILED DESCRIPTION

The drawings and descriptions provided herein should be regarded asillustrative in nature and not restrictive.

Any one or more of the teachings, expressions, aspects, examples, etc.described herein may be combined with any one or more of the otherteachings, expressions, aspects, examples, etc. that are describedherein. The following described teachings, expressions, aspects,examples, etc. should, therefore, not be viewed in isolation relative toeach other. Various suitable ways in which the teachings herein may becombined will be readily apparent to those of ordinary skill in the artin view of the teachings herein. Such modifications and variations areintended to be included within the scope of the claims.

The present disclosure provides the clinician an important new tool intheir therapeutic armamentarium: automatic detection and identificationof pharmaceutical agents actually delivered into the body. Theapplications of this new information device and system are multi-fold.By example, when used in concert with other medical sensing devices,correlation between drug delivery, batch and dosage can be correlated toa physiological response. In this manner, optimal pharma-therapeuticregimens may be formulated by the clinician.

Assessment of medications is made possible by the present disclosurewithout resort to awaiting overt clinical sequel of treatment, many ofwhich can be seriously adverse. By example, positive effects would bequickly ascertainable without being obscured by more random factors.Negative responses, such as changes in blood pressure, would becomeclearly evident as drug related or independent above backgroundphysiologic variation.

The ability to document the ingestion of a drug or other actual exposureof the body to a medication has many important clinical applications. Inthe simplest form, this technique provides accurate data of when a pillhas been taken and which pill has been taken. This allows the precisedetermination of which pill was taken at a specific point in time. Suchmonitoring capability assures patients are taking the prescribedmedication correctly. This information avoids the potential forover-prescription of medications that are not actually being taken.

The present disclosure provides the clinician an accurate dose responsecurve showing the response to a medication and the timing of theingestion of the pill. Such data has many applications. For instance,the clinician now has the ability to determine which patients have noresponse to the medicine in the pill. In a study situation, suchpatients can be removed from a study or a test of the clinical utilityof a certain medication. This provides that only people who have abeneficial response to a certain medication are retained in the trial.This feature will improve the efficacy of medications and to reduce theamount of medications that people take that are not being useful. It mayalso be used in trials to determine which patients actually consumed themedicine, and which did not.

In more standard clinical environments, this unique data allows carefulselection and titration of drug administration without resorting to moreovert physical symptoms to ascertain contraindications, efficacy, andoptimal dosage levels. The present disclosure provides a record foremergency room technicians or doctors when a patient is admitted to ahospital so that the patient's status can be accurately ascertained.Dosage events within the last hour or day prior to admission, and theidentity of the last medication, will be immediately available.

The clinician obtains this information through simple interrogation ofthe implanted or portable device. This device would tell them withoutany uncertainty what pills have been taken.

A “smart box” may be provided that can interrogate each pill andascertain its address. The box can write a distinctive product number orproduct code so that every single pill ever made is provided with aunique identifier. Fuses, for example, may be selectively destroyed sothe addresses may be detected electrically or optically. The presentdisclosure makes it possible to identify precisely who bought such apill from the authorized pharmacist.

Embodiments of the disclosure may include compositions having anidentifier stably associated therewith. In certain embodiments, thecompositions may be disrupted upon administration to a subject. As such,in certain embodiments, the compositions may be physically broken, e.g.,dissolved, degraded, eroded, etc., following delivery to a body, e.g.,via ingestion. The compositions of these embodiments may bedistinguished from devices that are configured to be ingested andsurvive transit through the gastrointestinal tract substantially, if notcompletely, intact. While the compositions of these embodiments may bethemselves disrupted upon administration, components of the composition,e.g., the identifier, may survive transit of the gastrointestinal tract,e.g., as described in greater detail below.

In certain embodiments, the compositions may include alisinopril/carrier component and an identifier. Each of these differentcomponents is reviewed separately in greater detail below.

Lisinopril/Carrier Component

The subject compositions may include a lisinopril/carrier component. Thelisinopril/carrier component may be a solid, which has an amount oflisinopril, e.g., a dosage, present in a pharmaceutically acceptablecarrier. The lisinopril/carrier component may be referred to as a“dosage formulation.”

As used herein, the term “IEM TAB” refers toingestible-event-marker-in-tablet, an identifier directly compressedwithin a tablet comprised of a drug-containing blend. In someembodiments, the IEM TAB may be about 45 to about 580 mg, about 50 mg,about 100 mg, about 200 mg, or about 550 mg.

As used herein, the term “SP TAB” refers to sensor-pill-in-tablet, anidentifier compressed within a tablet comprised of excipients (withoutdrug) that is further compressed into a drug containing blend utilizinga core tablet press (e.g., dry coat or mantle coat process). In someembodiments, the SP TAB may be about 225 to about 635 mg, about 235 mg,about 255 mg, or about 605 mg.

As used herein, the term “SP CAP” refers to sensor pill-in-capsule, anidentifier compressed within a tablet comprised of excipients (withoutdrug) that is further encapsulated with a drug-containing powder (e.g.,dry blend or granule), pellet, bead, mini-tablet, or tablet. In someembodiments, the SP CAP may be about 225 to about 615 mg, about 235 mg,about 285 mg, about 385 mg, or about 585 mg.

Lisinopril Compositions

“Lisinopril” produces a physiological result, e.g., a beneficial oruseful result, upon contact with a living organism, e.g., a mammal, suchas a human. Compositions provided herein comprise a lisinopril.Lisinopril may be referred to as, for example,(2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylicacid, PRINIVIL®, or ZESTRIL®.

Unless otherwise indicated, any reference to lisinopril herein bystructure or name includes: pharmaceutically acceptable salts; alternatesolid forms, such as polymorphs, solvates, hydrates, etc.; tautomers;deuterium-modified lisinoprils; or combinations thereof.

In some aspects, provided herein is a composition comprising lisinopril.In some embodiments, the composition is an ingestible event markercomposition comprising lisinopril.

In some embodiments, lisinopril as used herein may be present as apharmaceutically acceptable salt (e.g., a pharmaceutically acceptablesalt found in Remington's Pharmaceutical Sciences, Mace PublishingCompany, Philadelphia, Pa., 17th ed. 1985).

Lisinopril is an active pharmaceutical ingredient found in ZESTRIL®tablets to treat high blood pressure (hypertension) in adults andchildren above 6 years of age. In some embodiments, lisinopril as usedherein is a lisinopril dihydrate.

Lisinopril exhibits polymorphism. It has amorphous and crystallinehydrate forms such as lisinopril amorphous form, lisinopril monohydrate(form-I), lisinopril monohydrate (form-II), and lisinopril dihydrate. Insome embodiments, lisinopril as used herein is a lisinopril polymorph.In some embodiments, lisinopril as used herein is lisinopril amorphousform, lisinopril monohydrate (form-I), lisinopril monohydrate (form-II),or lisinopril dihydrate.

In some embodiments, the lisinopril compositions provided herein furthercomprise(2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxo-6,7,8,8a-tetrahydro-3H-pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoicacid (i.e. lisinopril diketopiperazine or lisinopril dihydrate impurityD), wherein the(2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxo-6,7,8,8a-tetrahydro-3H-pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoicacid is present in an amount of not more than about 0.001-0.30% byweight (e.g., not more than about 0.01-0.30%, 0.10-0.30%, 0.10-0.25%,0.15-0.30%, 0.20-0.30%, 0.25-0.30%, 0.001%, 0.01%, 0.10%, 0.15%, 0.20%,0.25%, or 0.30%). In some embodiments, the(2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxo-6,7,8,8a-tetrahydro-3H-pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoicacid is present in an amount of not more than about 0.001-0.30% byweight (e.g., not more than about 0.01-0.30%, 0.10-0.30%, 0.10-0.25%,0.15-0.30%, 0.20-0.30%, 0.25-0.30%, 0.001%, 0.01%, 0.10%, 0.15%, 0.20%,0.25%, or 0.30%) at about six months after the composition was prepared.

In some embodiments, the lisinopril compositions provided herein furthercomprise(2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxo-6,7,8,8a-tetrahydro-3H-pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoicacid, wherein the(2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxo-6,7,8,8a-tetrahydro-3H-pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoicacid is present in an amount of not more than about 0.001-0.10% byweight (e.g., not more than about 0.01-0.10%, 0.01-0.05%, 0.05-0.10%,0.001%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06% 0.07%, 0.08%, 0.09%, or0.10%). In some embodiments, the(2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxo-6,7,8,8a-tetrahydro-3H-pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoicacid is present in an amount of not more than about 0.001-0.10% byweight (e.g., not more than about 0.01-0.10%, 0.01-0.05%, 0.05-0.10%,0.001%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06% 0.07%, 0.08%, 0.09%, or0.10%) at about six months after the composition was prepared.

In some embodiments, the lisinopril compositions provided hereincomprise less than about 0.001%, independently, of2-amino-4-phenylbutanoic acid (lisinopril impurity A),4-Methylbenzenesulphonic acid (lisinopril impurity B),(2S)-2-[(3S,8aS)-3-(4-Aminobutyl)-1,4-dioxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenylbutanoicacid (lisinopril impurity C),2S)-1-[(2S)-6-Amino-2-[[(1R)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrole-2-carboxylic acid (lisinopril impurity E),(2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-cyclohexylpropyl]amino]hexanoyl]pyrrole-2-carboxylic acid (lisinopril impurity F),(S)-1-((S)-6-((S)-2-(((S)-6-Amino-1-((S)-2-carboxypyrrolidin-1-yl)-1-oxohexan-2-yl)amino)-4-phenylbutanamido)-2-(((S)-1-carboxy-3-phenylpropyl)amino)hexanoyl)pyrrolidine-2-carboxylicAcid (lisinopril impurity G), lisinopril dimer impurity H (C₃₇H₅₃N₅O₈),or lisinopril impurity I (C₃₁H₄₁N₃O₇). In some embodiments, thelisinopril compositions provided herein comprise less than about 0.001%,independently, of 2-amino-4-phenylbutanoic acid (lisinopril impurity A),4-Methylbenzenesulphonic acid (lisinopril impurity B),(2S)-2-[(3S,8aS)-3-(4-Aminobutyl)-1,4-dioxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenylbutanoicacid (lisinopril impurity C),2S)-1-[(2S)-6-Amino-2-[[(1R)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrole-2-carboxylic acid (lisinopril impurity E),(2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-cyclohexylpropyl]amino]hexanoyl]pyrrole-2-carboxylic acid (lisinopril impurity F),(S)-1-((S)-6-((S)-2-(((S)-6-Amino-1-((S)-2-carboxypyrrolidin-1-yl)-1-oxohexan-2-yl)amino)-4-phenylbutanamido)-2-(((S)-1-carboxy-3-phenylpropyl)amino)hexanoyl)pyrrolidine-2-carboxylicAcid (lisinopril impurity G), lisinopril dimer impurity H (C₃₇H₅₃N₅O₈),and lisinopril impurity I (C₃₁H₄₁N₃O₇).

As indicated above, in some embodiments a composition includinglisinopril provided herein may be present in a pharmaceuticallyacceptable vehicle or carrier, e.g., as described below. In someembodiments, the lisinopril may be present in an amount of from about0.1% to about 90% by weight, e.g., from about 0.1% to about 30% byweight, e.g., from about 1% to about 30% by weight, e.g., from about 1%to about 20% by weight, e.g. about 1%, about 2%, about 3%, about 4%,about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%,about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about18%, about 19%, about 20% by weight of the compositions, or a rangebounded by any two of these values.

In some embodiments, the composition comprises about 5 to about 80 mg oflisinopril. In some embodiments, the composition comprises about 5, 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 mg, or a rangebounded by any two of these values. In some embodiments, the compositioncomprises about 40 mg of lisinopril. In some embodiments, thecomposition comprises about 10 mg of lisinopril.

In some embodiments, the composition is encapsulated within a capsule.In some embodiments, the capsule is a gelatin capsule. In someembodiments, the capsule is a hydroxypropyl methyl cellulose capsule. Insome embodiments, the capsule is a size 2, 1, 0, 0 el, 00, 00 el, or 000capsule.

In some embodiments, the composition further comprises silicon,magnesium, copper (I) chloride, ethyl cellulose, and hydroxypropylcellulose.

In some embodiments, the composition further comprises silicon,aluminum, silicon dioxide, silicon nitride, titanium, titanium-tungsten,gold, magnesium, copper (I) chloride, hydroxypropyl cellulose, ethylcellulose, triethyl citrate, or a combination thereof. In someembodiments, the silicon, aluminum, silicon dioxide, silicon nitride,titanium, titanium-tungsten, gold, magnesium, copper (I) chloride,hydroxypropyl cellulose, ethyl cellulose, triethyl citrate, or acombination thereof is in an identifier.

In some embodiments, the identifier comprises an integrated circuit, awafer, and a skirt film. In some embodiments, the identifier furthercomprises a coating that coats the circuit, wafer and skirt film. Insome embodiments, the identifier is about 0.5% to about 5% w/w of thecomposition. In some embodiments, the identifier is about 0.5% w/w ofthe composition. In some embodiments, the identifier is about 1% w/w ofthe composition. In some embodiments, the identifier is about 1.5% w/wof the composition. In some embodiments, the identifier is about 2% w/wof the composition. In some embodiments, the identifier is about 2.5%w/w of the composition. In some embodiments, the identifier is about 3%w/w of the composition. In some embodiments, the identifier is about3.5% w/w of the composition. In some embodiments, the identifier isabout 4% w/w of the composition. In some embodiments, the identifier isabout 4.5% w/w of the composition. In some embodiments, the identifieris about 5% w/w of the composition. In some embodiments, the identifieris about 6%, 7%, 8%, 9% or 10% w/w of the composition. In someembodiments, the identifier is about 3, 4, 5, 6, 7, 8, 9, or 10 mg. Insome embodiments, the identifier is about 3.8 to about 4.1 mg. In someembodiments, the identifier is about 3.92 mg.

In some embodiments, the integrated circuit comprises silicon, aluminum,silicon dioxide, silicon nitride, or a combination thereof. In someembodiments, the integrated circuit comprises silicon, aluminum, silicondioxide, and silicon nitride.

In some embodiments, the wafer comprises titanium, titanium-tungsten,gold, magnesium, copper (I) chloride, hydroxypropyl cellulose, or acombination thereof. In some embodiments, the wafer comprises titanium,titanium-tungsten, gold, magnesium, copper (I) chloride, andhydroxypropyl cellulose.

In some embodiments, the skirt film comprises ethyl cellulose,hydroxypropyl cellulose, triethyl citrate, or a combination thereof. Insome embodiments, the skirt film comprises ethyl cellulose,hydroxypropyl cellulose, and triethyl citrate.

In some embodiments, the coating comprises hydroxypropyl cellulose.

In some embodiments, the identifier comprises about 15 to about 25% w/wintegrated circuit. In some embodiments, the identifier comprises about18 to about 21% w/w integrated circuit. In some embodiments, theidentifier comprises about 19.5% w/w integrated circuit. In someembodiments, the identifier comprises about 2 to about 4% w/w wafer. Insome embodiments, the identifier comprises about 3.1% w/w wafer. In someembodiments, the identifier comprises about 65 to about 75% w/w skirtfilm. In some embodiments, the identifier comprises about 70 to about73% w/w skirt film. In some embodiments, the identifier comprises about71.5% w/w skirt film. In some embodiments, the identifier comprisesabout 4 to about 7% w/w coating. In some embodiments, the identifiercomprises about 5.5 to about 6.5% w/w coating. In some embodiments, theidentifier comprises about 5.9% w/w coating.

In some embodiments, the composition further comprises about 0.5% toabout 1% w/w magnesium stearate. In some embodiments, the compositioncomprises about 0.5% w/w magnesium stearate. In some embodiments, thecomposition comprises about 1% w/w magnesium stearate.

In some embodiments, the composition further comprises about 5% to about20% w/w pregelatinized starch. In some embodiments, the compositionfurther comprises about 5% to about 10% w/w pregelatinized starch. Insome embodiments, the composition further comprises about 10% to about20% w/w pregelatinized starch. In some embodiments, the compositioncomprises about 5% w/w pregelatinized starch. In some embodiments, thecomposition comprises about 10% w/w pregelatinized starch. In someembodiments, the composition comprises about 15% w/w pregelatinizedstarch. In some embodiments, the composition comprises about 20% w/wpregelatinized starch.

In some embodiments, the composition further comprises about 15% toabout 30% w/w microcrystalline cellulose. In some embodiments, thecomposition further comprises about 15% w/w microcrystalline cellulose.In some embodiments, the composition further comprises about 30% w/wmicrocrystalline cellulose.

In some embodiments, the composition further comprises about 0% to about2% w/w croscarmellose sodium. In some embodiments, the compositioncomprises about 1% to about 2% w/w croscarmellose sodium. In someembodiments, the composition comprises about 2% w/w croscarmellosesodium.

In some embodiments, the composition further comprises about 20% toabout 30% w/w mannitol (e.g., 50 μm). In some embodiments, thecomposition comprises about 24% to about 25% w/w mannitol (e.g., 50 μm).In some embodiments, the composition comprises about 24.6% w/w mannitol(e.g., 50 μm).

In some embodiments, the composition further comprises about 15% toabout 30% w/w dicalcium phosphate dihydrate. In some embodiments, thecomposition further comprises about 15% w/w dicalcium phosphatedihydrate. In some embodiments, the composition further comprises about30% w/w dicalcium phosphate dihydrate.

In some embodiments, the lisinopril is present in the composition inabout 7.3% w/w.

In some embodiments, the composition further comprises about 0.10% toabout 0.20% w/w iron oxide yellow. In some embodiments, the compositioncomprises about 0.10% to about 0.15% w/w iron oxide yellow. In someembodiments, the composition comprises about 0.15% to about 0.20% w/wiron oxide yellow. In some embodiments, the composition comprises about0.15% w/w iron oxide yellow.

In some embodiments, the composition further comprises 0.5% to about 1%w/w magnesium stearate, 0% to about 2% w/w croscarmellose sodium, and aningestible event marker.

In some embodiments, the lisinopril is in a granule comprising: thelisinopril, dicalcium phosphate dihydrate, mannitol (e.g., 180 μm), andpregelatinized starch. In some embodiments, the granule furthercomprises iron oxide yellow or water, or both.

In some embodiments, the granule comprises about 8% to about 14% w/wlisinopril. In some embodiments, the granule comprises about 10% toabout 12% w/w lisinopril. In some embodiments, the granule comprisesabout 10.3% to about 11.3% w/w lisinopril. In some embodiments, thegranule comprises about 10.3% w/w lisinopril. In some embodiments, thegranule comprises about 11.2% w/w lisinopril. In some embodiments, thecomposition comprises about 40 mg of lisinopril.

In some embodiments, the granule comprises about 14% to about 18% w/wdicalcium phosphate dihydrate. In some embodiments, the granulecomprises about 15% to about 17% w/w dicalcium phosphate dihydrate. Insome embodiments, the granule comprises about 15.4% to about 16.9% w/wdicalcium phosphate dihydrate. In some embodiments, the granulecomprises about 15.5% w/w dicalcium phosphate dihydrate. In someembodiments, the granule comprises about 16.9% w/w dicalcium phosphatedihydrate.

In some embodiments, the granule comprises about 55% to about 65% w/wmannitol (e.g., 180 μm). In some embodiments, the granule comprisesabout 57% to about 62% w/w mannitol (e.g., 180 μm). In some embodiments,the granule comprises about 58% to about 61% w/w mannitol (e.g., 180μm). In some embodiments, the granule comprises about 58% ow/w mannitol(e.g., 180 μm). In some embodiments, the granule comprises about 61% w/wmannitol (e.g., 180 μm). In some embodiments, the granule comprisesabout 58.6% w/w mannitol (e.g., 180 μm). In some embodiments, thegranule comprises about 61.5% w/w mannitol (e.g., 180 μm).

In some embodiments, the granule comprises about 9% to about 18% w/wpregelatinized starch. In some embodiments, the granule comprises about10% to about 17% w/w pregelatinized starch. In some embodiments, thegranule comprises about 11% to about 16% w/w pregelatinized starch. Insome embodiments, the granule comprises about 11% w/w pregelatinizedstarch. In some embodiments, the granule comprises about 11.2% w/wpregelatinized starch. In some embodiments, the granule comprises about16% w/w pregelatinized starch. In some embodiments, the granulecomprises about 15.5% w/w pregelatinized starch.

In some embodiments, the granule comprises about 0.10% to about 0.20%w/w iron oxide yellow. In some embodiments, the granule comprises about0.10% to about 0.15% w/w iron oxide yellow. In some embodiments, thegranule comprises about 0.15% to about 0.20% w/w iron oxide yellow. Insome embodiments, the granule comprises about 0.15% w/w iron oxideyellow.

In some embodiments, the granule comprises about 10.3% w/w lisinopril,about 15.5% w/w dicalcium phosphate, about 58.6% w/w mannitol (e.g., 180μm), and about 15.5% w/w pregelatinized starch. In some embodiments, thegranule comprises about 10.3% w/w lisinopril, about 15.5% w/w dicalciumphosphate, about 58.6% w/w mannitol (e.g., 180 μm), about 15.5% w/wpregelatinized starch, and about 0.15% w/w iron oxide yellow.

In some embodiments, the granule comprises about 11.2% w/w lisinopril,about 16.9% w/w dicalcium phosphate, about 60.5% w/w mannitol (e.g., 180μm), and about 11.2% w/w pregelatinized starch. In some embodiments, thegranule comprises about 11.2% w/w lisinopril, about 16.9% w/w dicalciumphosphate, about 60.5% w/w mannitol (e.g., 180 μm), about 11.2% w/wpregelatinized starch, and about 0.15% w/w iron oxide yellow.

In some embodiments, the composition comprises about 4.5% to about 18.5%w/w lisinopril (e.g., about 5, 10, or 18.2% w/w), about 13.0% to about16.0% ow/w dicalcium phosphate (e.g., about 28.0, 30.5, 13.2, or 14.3%w/w), about 10.5% to about 59.0% w/w mannitol (e.g., about 22.9, 25.6,47.5, or 51.4% w/w), about 4.5% to about 20.5% w/w pregelatinized starch(e.g., about 5, 20, or 22% w/w), about 0% to about 30.0% w/wmicrocrystalline cellulose (e.g., about 0 or 16% w/w), about 0% to about2.5% w/w croscarmellose sodium (e.g., about 0 or 2% w/w), about 0% toabout 0.20% w/w iron oxide (e.g., about 0.14 or 0.15% w/w), about 0% toabout 0.30% w/w FD&C yellow #6 (e.g., about 0% w/w), wherein thelisinopril, dicalcium phosphate, mannitol, pregelatinized starch,microcrystalline cellulose, croscarmellose sodium, iron oxide, and FD&Cyellow #6 are in a granule, and about 0% to about 10.5% w/wextragranular pregelatinized starch (e.g., about 0 or 10% w/w), andabout 0% to about 1.5% w/w extra granular magnesium stearate (e.g.,about 1% w/w).

In some embodiments, the composition comprises a composition provided inTable 1, Table 3 (e.g., B5, A5, A4, A4+AcDiSol, A4+Starch, A5+Starch,A6a, A6b, B6, A4a, A4b, A4c, A4d, A4e, A4f, A5a, A5b), or Table 4 (e.g.,B6 (F), B6 (P), B7 (P), A6-a (P), or A6-b (F)). In some embodiments, thecomposition comprises a core formulation provided herein (such as one ofthose described in Example 6 or Table 2 (e.g., core 1, 2, 3, 4, 5, 6, 7,8, or 9)).

In some embodiments, the composition comprises a granule and anidentifier encapsulated in a capsule. In some embodiments, thecomposition comprises a plurality of granules.

In some embodiments, the composition comprises:

1) about 92 to about 99.3% w/w of a granule comprising:

-   -   about 10.3% w/w lisinopril;    -   about 15.5% w/w dicalcium phosphate;    -   about 58.6% w/w mannitol (e.g., 180 μm); and    -   about 15.5% w/w pregelatinized starch; and

2) about 0.7 to about 8% w/w of an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule and identifier areencapsulated within a capsule (e.g., a gelatin or hydroxypropylmethylcellulose capsule).

In some embodiments, the ingestible event marker composition comprises:

1) about 89 to about 98.8% w/w of a granule comprising:

-   -   about 10.3% w/w lisinopril;    -   about 15.5% w/w dicalcium phosphate;    -   about 58.6% w/w mannitol (e.g., 180 μm);    -   about 15.5% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow;

2) about 0.7 to about 8% w/w of an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

3) about 0.5% to about 1% w/w magnesium stearate; and

4) about 0% to about 2% w/w croscarmellose sodium; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier magnesiumstearate, and croscarmellose sodium are encapsulated within a capsule(e.g., a gelatin or hydroxypropyl methylcellulose capsule).

In some embodiments, the ingestible event marker composition comprises:

1) about 75.5 to about 90.9% w/w of a granule comprising:

-   -   about 10.3% w/w lisinopril;    -   about 15.5% w/w dicalcium phosphate;    -   about 58.6% w/w mannitol (e.g., 180 μm);    -   about 15.5% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow;

2) about 8.6 to about 22% w/w sensor pill comprising:

-   -   a) about 90% w/w microcrystalline cellulose;    -   b) about 1.8% w/w croscarmellose sodium;    -   c) about 0.5% w/w magnesium stearate; and    -   c) about 8% w/w of an identifier comprising:        -   a1) an integrated circuit comprising silicon, aluminum,            silicon dioxide, and silicon nitride;        -   b1) a wafer comprising titanium, titanium-tungsten, gold,            magnesium, copper (I) chloride, and hydroxypropyl cellulose;            and        -   c1) a skirt film comprising ethyl cellulose, hydroxypropyl            cellulose, and triethyl citrate;

3) about 0.5 to about 2.5% w/w of an excipient additive comprising:

-   -   about 20% to about 100% w/w magnesium stearate; and    -   about 0% to about 80% w/w croscarmellose sodium; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, sensor pill, andexcipient additive are encapsulated within a capsule (e.g., a gelatin orhydroxypropyl methylcellulose capsule).

In some embodiments, the ingestible event marker composition comprises:

1) about 86.5 to about 93.8% w/w of a granule comprising:

-   -   about 10.3% w/w lisinopril;    -   about 15.5% w/w dicalcium phosphate;    -   about 58.6% w/w mannitol (e.g., 180 μm);    -   about 15.5% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow;

2) about 0.7 to about 8% w/w of an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

3) about 0.5% w/w magnesium stearate; and

4) about 5% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier magnesiumstearate, and pregelatinized starch are encapsulated within a capsule(e.g., a gelatin or hydroxypropyl methylcellulose capsule).

In some embodiments, the ingestible event marker composition comprises:

1) about 72.5 to about 85.9% w/w of a granule comprising:

-   -   about 10.3% w/w lisinopril;    -   about 15.5% w/w dicalcium phosphate;    -   about 58.6% w/w mannitol (e.g., 180 μm);    -   about 15.5% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow;

2) about 8.6 to about 22% w/w sensor pill comprising:

-   -   a) about 90% w/w microcrystalline cellulose;    -   b) about 1.8% w/w croscarmellose sodium;    -   c) about 0.5% w/w magnesium stearate; and    -   c) about 8% w/w of an identifier comprising:        -   a1) an integrated circuit comprising silicon, aluminum,            silicon dioxide, and silicon nitride;        -   b1) a wafer comprising titanium, titanium-tungsten, gold,            magnesium, copper (I) chloride, and hydroxypropyl cellulose;            and        -   c1) a skirt film comprising ethyl cellulose, hydroxypropyl            cellulose, and triethyl citrate;

3) about 5.5% w/w of an excipient additive comprising:

-   -   about 9% w/w magnesium stearate; and    -   about 910% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier, andexcipient additive are encapsulated within a capsule (e.g., a gelatin orhydroxypropyl methylcellulose capsule).

In some embodiments, the composition comprises:

1) about 92 to about 99.3% w/w of a granule comprising:

-   -   about 11.2% w/w lisinopril;    -   about 16.9% w/w dicalcium phosphate;    -   about 60.5% w/w mannitol (e.g., 180 μm); and    -   about 11.2% w/w pregelatinized starch; and

2) about 0.7 to about 8% w/w of an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule and identifier areencapsulated within a capsule (e.g., a gelatin or hydroxypropylmethylcellulose capsule).

In some embodiments, the ingestible event marker composition comprises:

1) about 81.5 to about 93.8% w/w of a granule comprising:

-   -   about 11.2% w/w lisinopril;    -   about 16.9% w/w dicalcium phosphate;    -   about 60.5% w/w mannitol (e.g., 180 μm);    -   about 11.2% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow; and

2) about 0.7 to about 8% w/w of an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

3) about 0.5% w/w magnesium stearate; and

4) about 5 to about 10% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier, magnesiumstearate, and pregelatinized starch are encapsulated within a capsule(e.g., a gelatin or hydroxypropyl methylcellulose capsule).

In some embodiments, the ingestible event marker composition comprises:

1) about 67.5 to about 85.9% w/w of a granule comprising:

-   -   about 11.2% w/w lisinopril;    -   about 16.9% w/w dicalcium phosphate;    -   about 60.5% w/w mannitol (e.g., 180 μm);    -   about 11.2% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow; and

2) about 8.6 to about 22% w/w of a sensor pill comprising:

-   -   a) about 90% w/w microcrystalline cellulose;    -   b) about 1.8% w/w croscarmellose sodium;    -   c) about 0.5% w/w magnesium stearate; and    -   c) about 8% w/w of an identifier comprising:        -   a1) an integrated circuit comprising silicon, aluminum,            silicon dioxide, and silicon nitride;        -   b1) a wafer comprising titanium, titanium-tungsten, gold,            magnesium, copper (I) chloride, and hydroxypropyl cellulose;            and        -   c1) a skirt film comprising ethyl cellulose, hydroxypropyl            cellulose, and triethyl citrate;

3) about 5.5 to about 10.5% w/w of an excipient additive comprising:

-   -   about 5 to about 9% w/w magnesium stearate; and    -   about 910% to about 95% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, sensor pill, andexcipient additive are encapsulated within a capsule (e.g., a gelatin orhydroxypropyl methylcellulose capsule).

In some embodiments, the ingestible event marker composition comprises:

1) about 86.5 to about 93.8% w/w of a granule comprising:

-   -   about 11.2% w/w lisinopril;    -   about 16.9% w/w dicalcium phosphate;    -   about 60.5% w/w mannitol (e.g., 180 μm);    -   about 11.2% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow; and

2) about 0.7 to about 8% w/w of an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

3) about 0.5% w/w magnesium stearate; and

4) about 5% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier, magnesiumstearate, and pregelatinized starch are encapsulated within a capsule(e.g., a gelatin or hydroxypropyl methylcellulose capsule).

In some embodiments, the ingestible event marker composition comprises:

1) about 72.5 to about 85.9% w/w of a granule comprising:

-   -   about 11.2% w/w lisinopril;    -   about 16.9% w/w dicalcium phosphate;    -   about 60.5% w/w mannitol (e.g., 180 μm);    -   about 11.2% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow; and

2) about 8.6 to about 22% w/w of a sensor pill comprising:

-   -   a) about 90% w/w microcrystalline cellulose;    -   b) about 1.8% w/w croscarmellose sodium;    -   c) about 0.5% w/w magnesium stearate; and    -   c) about 8% w/w of an identifier comprising:        -   a1) an integrated circuit comprising silicon, aluminum,            silicon dioxide, and silicon nitride;        -   b1) a wafer comprising titanium, titanium-tungsten, gold,            magnesium, copper (I) chloride, and hydroxypropyl cellulose;            and        -   c1) a skirt film comprising ethyl cellulose, hydroxypropyl            cellulose, and triethyl citrate;

3) about 5.5% w/w of an excipient additive comprising:

-   -   about 9% w/w magnesium stearate; and    -   about 910% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, sensor pill, andexcipient additive are encapsulated within a capsule (e.g., a gelatin orhydroxypropyl methylcellulose capsule).

In some embodiments, the composition is in a compressed tablet form. Insome embodiments, the compressed tablet comprises an inner compressedtablet encapsulated (e.g. dry coated or mantle coated) within an outercompressed shell.

In some embodiments, the ingestible event marker composition comprises:

about 7.3% w/w lisinopril;

about 30.0% w/w dicalcium phosphate dihydrate (di-tab);

about 24.6% w/w mannitol (e.g., 50 μm);

about 20.0% w/w pregelatinized starch;

about 15.0% w/w microcrystalline cellulose;

about 2.0% w/w croscarmellose sodium;

about 0.15% w/w yellow iron oxide;

about 1.0% w/w magnesium stearate; and

an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating.

In some embodiments, the ingestible event marker composition comprises:

about 7.3% w/w lisinopril;

about 15.0% w/w dicalcium phosphate dihydrate (di-tab);

about 24.6% w/w mannitol (e.g., 50 μm);

about 20.0% w/w pregelatinized starch;

about 30.0% w/w microcrystalline cellulose;

about 2.0% w/w croscarmellose sodium;

about 0.15% w/w yellow iron oxide;

about 1.0% w/w magnesium stearate; and

an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating.

In some embodiments, the ingestible event marker composition comprises:

about 7.3% w/w lisinopril;

about 30.0% w/w dicalcium phosphate dihydrate (di-tab);

about 24.6% w/w mannitol (e.g., 50 μm);

about 20.0% w/w pregelatinized starch;

about 15.0% w/w microcrystalline cellulose;

about 2.0% w/w croscarmellose sodium;

about 0.15% w/w yellow iron oxide;

about 1.0% w/w magnesium stearate; and

an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein

the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating,

the lisinopril, dicalcium phosphate dihydrate, mannitol (e.g., 50 μm),pregelatinized starch, microcrystalline cellulose, croscarmellosesodium, yellow iron oxide, and identifier are compressed to form aninner compressed tablet, and

the magnesium stearate is compressed as an outer compressed shellencapsulating the inner compressed tablet.

In some embodiments, the ingestible event marker composition comprises:

about 7.3% w/w lisinopril;

about 15.0% w/w dicalcium phosphate dihydrate (di-tab);

about 24.6% w/w mannitol (e.g., 50 μm);

about 20.0% w/w pregelatinized starch;

about 30.0% w/w microcrystalline cellulose;

about 2.0% w/w croscarmellose sodium;

about 0.15% w/w yellow iron oxide;

about 1.0% w/w magnesium stearate; and

an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein

the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating,

the lisinopril, dicalcium phosphate dihydrate, mannitol (e.g., 50 μm),pregelatinized starch, microcrystalline cellulose, croscarmellosesodium, yellow iron oxide, and identifier are compressed to form aninner compressed tablet, and

the magnesium stearate is compressed as an outer compressed shellencapsulating the inner compressed tablet.

Identifiers

Also present in the subject compositions is an identifier. Theidentifier may vary depending on the particular embodiment and intendedapplication of the composition. In certain embodiments, the identifiermay be a component that emits a signal upon activation by a stimulus,e.g., by interrogation, upon contact with a target physiologicallocation, etc. As such, the identifier may be an identifier that emits asignal when it contacts a target body (i.e., physiological) site. Inaddition or alternatively, the identifier may be an identifier thatemits a signal when interrogated.

In yet other embodiments, the identifier may be an inert, butidentifiable marker, e.g., an engraved identifier (such as one that isfabricated from a material or materials that survive digestion). Thismarker may then be identified, for example, following an autopsy orforensic examination. It is possible to provide a more internal devicewithin a pill to determine both that its surface has partially beensubject to digestion, but also that the inner pill material has alsobeen digested. This application may be particularly useful inexperimental pharmacological settings. The identifier of theseembodiments may be one that does not necessarily emit a signal, butwhich can be optically inspected, e.g., visually or machine read, toobtain information about the composition with which it was associatedprior to administration.

While the identifier may be an identifier that does not emit a signal,in certain embodiments, as summarized above, the identifier may be onethat does emit a signal. Depending on the needs of a particularapplication, the signal may be a generic signal, e.g., a signal thatmerely identifies that the composition has contacted the target site, ora unique signal, e.g., a signal which in some way uniquely identifiesthat a particular composition from a group or plurality of differentcompositions in a batch has contacted a target physiological site. Assuch, the identifier may be one that, when employed in a batch of unitdosages, e.g., a batch of tablets, may emit a signal which cannot bedistinguished from the signal emitted by the identifier of any otherunit dosage member of the batch. In yet other embodiments, theidentifier may emit a signal that uniquely identifies a given unitdosage, even from other identical unit dosages in a given batch.Accordingly, in certain embodiments, the identifier may emit a uniquesignal that distinguishes a given type of unit dosage from other typesof unit dosages, e.g., a given medication from other types ofmedications. In certain embodiments, the identifier may emit a uniquesignal that distinguishes a given unit dosage from other unit dosages ofa defined population of unit dosages, e.g., a prescription, a batch or alifetime production run of dosage formulations. In certain embodiments,the identifier may emit a signal that is unique, i.e., distinguishable,from a signal emitted by any other dosage formulation ever produced,where such a signal may be viewed as a universally unique signal (e.g.,analogous to a human fingerprint which is distinct from any otherfingerprint of any other individual and therefore uniquely identifies anindividual on a universal level). In one embodiment, the signal mayeither directly convey information about the composition, or provide anidentifying code, which may be used to retrieve information about thecomposition from a database, i.e., a database linking identifying codeswith compositions.

The identifier may be any component or device that is capable ofgenerating a detectable signal following activation in response to astimulus. In certain embodiments, the stimulus may activate theidentifier to emit a signal once the composition comes into contact witha physiological target site, e.g., as summarized above. For example, apatient may ingest a pill that upon contact with the stomach fluids,generates a detectable signal. Depending on the embodiment, the targetphysiological site or location may vary, where representative targetphysiological sites of interest include, but are not limited to: alocation in the gastrointestinal tract (such as the mouth, esophagus,stomach, small intestine, large intestine, etc.); another locationinside the body, such as a parental location, vascular location, etc.;or a topical location; etc.

In certain embodiments, the stimulus that activates the identifier maybe an interrogation signal, such as a scan or other type ofinterrogation. In these embodiments, the stimulus may activate theidentifier, thereby emitting a signal which may then be received andprocessed, e.g., to identify the composition in some manner.

In certain of these embodiments, the identifier may include a powersource that transduces broadcast power and a signal generating elementthat modulates the amount of transduced power, such that a signal is notemitted from the identifier but instead the amount of broadcast powertransduced by the identifier is detected and employed as the “signal.”Such embodiments may be useful in a variety of applications, such asapplications where the history of a given composition may be ofinterest, e.g., as reviewed in greater detail below.

In certain embodiments, the identifier may be dimensioned to becomplexed with the lisinopril/pharmaceutically acceptable carriercomponent to produce a composition that can be readily administered to asubject in need thereof. As such, in certain embodiments, the identifierelement may be dimensioned to have a width ranging from about 0.05 mm toabout 1 mm, such as from about 0.1 mm to about 0.2 mm; a length rangingfrom about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2mm and a height ranging from about 0.1 mm to about 1 mm, such as fromabout 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2mm. In certain embodiments, the identifier may be 1 mm³ or smaller, suchas 0.1 mm³ or smaller, including 0.2 mm³ or smaller. The identifierelement may take a variety of different configurations, such as but notlimited to: a chip configuration, a cylinder configuration, a sphericalconfiguration, a disc configuration, etc., where a particularconfiguration may be selected based on intended application, method ofmanufacture, etc.

The identifier may generate a variety of different types of signals,including but not limited to, RF, magnetic, conductive (near field),acoustic, etc.

In certain embodiments, the identifier may be one that is programmablefollowing manufacture, in the sense that the signal generated by theidentifier may be determined after the identifier is produced, where theidentifier may be field programmable, mass programmable, fuseprogrammable, and even reprogrammable. Such embodiments are of interestwhere uncoded identifiers are first produced and following incorporationinto a composition are then coded to emit an identifying signal for thatcomposition. Any convenient programming technology may be employed. Incertain embodiments, the programming technology employed is RFIDtechnology. RFID smart tag technology of interest that may be employedin the subject identifiers includes, but is not limited to: thatdescribed in U.S. Pat. Nos. 7,035,877; 7,035,818; 7,032,822; 7,031,946,as well as published application no. US20050131281, and the like, thedisclosures of which are herein incorporated by reference. With RFID orother smart tag technology, a manufacturer/vendor may associate a uniqueID code with a given identifier, even after the identifier has beenincorporated into the composition. In certain embodiments, eachindividual or entity involved in the handling of the composition priorto use may introduce information into the identifier, e.g., in the formof programming with respect to the signal emitted by the identifier,e.g., as described in U.S. Pat. No. 7,031,946 the disclosure of which isherein incorporated by reference.

The identifier of certain embodiments may include a memory element,where the memory element may vary with respect to its capacity. Incertain embodiments, the memory element may have a capacity ranging fromabout 1 bit to 1 gigabyte or more, such as 1 bit to 1 megabyte,including from about 1 bit to about 128 bit. The particular capacityemployed may vary depending on the application, e.g., whether the signalis a generic signal or coded signal, and where the signal may or may notbe annotated with some additional information, e.g., name of lisinopril,etc.

Identifier components of embodiments of the disclosure may have: (a) anactivation component and (b) a signal generation component, where thesignal generation component is activated by the activation component toproduce an identifying signal, e.g., as described above.

Activation Component

The activation component may be a component that activates the signalgeneration element to emit a signal upon experience of a stimulus, e.g.,contact of the composition with a target physiological site of interest,such as the stomach. The activation component may be integrated with apower source, e.g., a battery. Illustrative activation approaches mayinclude, but are not limited to: Battery Completion, e.g., Batteryactivated by electrolyte addition and Battery activated by cathode oranode addition; Battery connection, e.g., Battery activated by conductoraddition; Transistor-mediated Battery Connection, e.g., Batteryactivated by transistor gate, Geometry Modification, Detection ofGeometry Modification by Resonant Structure, Pressure Detection,Resonant Structure Modification; etc.

Battery/Power Source

In certain embodiments, the power source may be turned on upon contactof the power source with a target site, e.g., a physiological targetsite, such as the stomach, e.g., stomach acid. In certain embodiments,the power source may be a battery that is turned on to provide powerupon contact with the physiological target site, where the battery iscoupled to the signal generation component such that when the battery isturned on, the signal generation component may emit the identifyingsignal.

In certain embodiments, the battery that is employed may be one thatcomprises the two dissimilar materials magnesium metal and copperchloride (e.g., copper (I) chloride, CuCl, or cuprous chloride), whichconstitute the two electrodes of the battery. In certain embodiments,these two materials may be shielded from the surrounding environment byan additional layer of material. When the shielding material (e.g.,lisinopril/carrier matrix), is dissolved or eroded by the surroundingfluid, the electrode materials may be exposed and come in contact withthe body fluid, such as stomach acid or other types of electrolytefluid. A potential difference, that is, a voltage, may be generatedbetween the electrodes as a result of the respective oxidation andreduction reactions incurred to the two electrode materials. A voltaiccell, or battery, can be thereby formed. Accordingly, in someembodiments of the disclosure, such batteries may be configured suchthat when the two dissimilar materials are exposed to the target site,e.g., the stomach, the digestive tract, etc., during the physical andchemical erosion of the composition in which the signal generationelement is present, a voltage may be generated. In such embodiments, thepower source described above is not a “battery” in the common sense ofthe word, but rather as defined in the discipline of physics. The twodissimilar materials (magnesium metal and copper chloride) in anelectrolyte may be at different potentials. As a result, a potentialdifference between the two dissimilar materials may be generated.

Various battery-activation configurations are possible. Representativetypes of cell-activation approaches may include, but are not limited to:activation by presence of electrolyte, activation by presence of acathode material, activation by presence of a conductive material.

After the battery is activated, further activation configurations can beemployed to activate the signal generation component. For example, thesignal generation component can be activated through the activation ofthe gate of a metal oxide semiconductor (MOS) circuit, such as a CMOSswitch. Activation of the gate of the MOS circuit can be based on one ormore parameters, which may include but are not limited to: gate current,gate charge, and gate capacitance.

The gate current, for activation purposes, can be a function of theconductivity of surrounding body fluids or tissues. Such conductivitycan further be a function of one or more parameters, which may includebut are not limited to: solution concentration, solution pH value, ioniccontent of solution, enzymatic content of solution, temperature, andcarrier mobility. Carrier mobility can also be a function oftemperature.

Similarly, the gate charge can be a function of one or more parameters,which may include but are not limited to: solution composition, crystalpotential, electrical potential, gravitational potential, gatecapacitance, and carrier concentration. The carrier concentration canalso be a function of temperature.

The gate capacitance can be a function of the capacitive geometry of thegate, which can further be a function of pressure, a resonant input, orthe characteristics of a dielectric material coupled to the gate. Thecharacteristics of the dielectric material can vary with one or moreparameters, which may include but are not limited to: chemical contentsof a digestive tract, chemical character of a physiological location,and amount of dissolution of the dielectric material in body fluids.

In certain embodiments, the battery may be one that is made up of activeelectrode materials, electrolyte, and inactive materials, such ascurrent collectors, packaging, etc. The active materials are a pair madeup of magnesium metal and copper chloride.

The electrode materials provided herein are copper chloride (e.g.,copper (I) chloride, CuCl, or cuprous chloride) as the cathode andmagnesium metal as the anode.

Some embodiments of the batteries described herein provide for a voltageupon contact with the target physiological site, e.g., the stomach,sufficient to drive the signal generation element of the identifier. Incertain embodiments, the voltage provided by the electrode materialsupon contact of the metals of the power source with the targetphysiological site may be 0.001 V or higher, including 0.01 V or higher,such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5 volts orhigher, and including 1.0 volts or higher, where in certain embodiments,the voltage may range from about 0.001 to about 10 volts, such as fromabout 0.01 to about 10 V.

In certain embodiments, the batteries may have a small form factor.Batteries may be 10 mm³ or smaller, such as 1.0 mm³ or smaller,including 0.1 mm³ or smaller, including 0.02 mm³ or smaller. As such, incertain embodiments, the battery element is dimensioned to have a widthranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm toabout 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such asfrom about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mmto about 1 mm, such as from about 0.05 mm to about 0.3 mm, includingfrom about 0.1 mm to about 0.2 mm.

In certain embodiments, the battery may have a split or segmentedconfiguration.

In certain embodiments, the battery may be one free of packaging. Assuch, the electrodes may be exposed and not protected by any protectingor sealing structure. As such, following removal of thelisinopril/carrier matrix material with which the battery may beassociated, the battery per se does not itself include a protectivepackaging such that the electrodes may be free to contact theelectrolyte at the target physiological location.

In certain embodiments, the battery power source may be viewed as apower source that exploits reverse electrolysis in an ionic solutionsuch as gastric fluid, blood, or other bodily fluids and some tissues.

Where the power source is a battery, the battery may be fabricated in anumber of different ways. In certain embodiments, fabrication protocolswhich may be categorized as “planar” processing protocols are employed,as developed in greater detail below.

Signal Generation Component

The signal generation component of the identifier element is a structurethat, upon activation by the activation component, may emit a detectablesignal, e.g., that can be received by a receiver. The signal generationcomponent of certain embodiments can be any convenient device that iscapable of producing a detectable signal and/or modulating transducedbroadcast power, upon activation by the activation component. Detectablesignals of interest include, but are not limited to: conductive signals,acoustic signals, etc. As reviewed above, the signals emitted by thesignal generator may be generic or unique signals, where representativetypes of signals of interest include, but are not limited to: frequencyshift coded signals; amplitude modulation signals; frequency modulationsignals; etc.

In certain embodiments, the signal generation element may includecircuitry which produces or generates the signal. The type of circuitrychosen may depend, at least in part, on the driving power that issupplied by the power source of the identifier. For example, where thedriving power is 1.2 volts or above, standard CMOS circuitry may beemployed. In other embodiments where the driving power ranges from about0.7 to about 1.2 V, sub-threshold circuit designs may be employed. Fordriving powers of about 0.7 V or less, zero-threshold transistor designsmay be employed.

In certain embodiments, the signal generation component includes avoltage-controlled oscillator (VCO) that can generate a digital clocksignal in response to activation by the activation component. The VCOcan be controlled by a digital circuit, which is assigned an address andwhich can control the VCO with a control voltage. This digital controlcircuit can be embedded onto a chip that includes the activationcomponent and oscillator. Using phase shift keying to encode theaddress, an identifying signal can be transmitted.

The signal generation component may include a distinct transmittercomponent that serves to transmit the generated signal to a remotereceiver, which may be internal or external to the patient, as reviewedin greater detail below. The transmitter component, when present, maytake a number of different configurations, e.g., depending on the typeof signal that is generated and is to be emitted. In certainembodiments, the transmitter component may be made up of one or moreelectrodes. In certain embodiments, the transmitter component may bemade up of one or more wires, e.g., in the form of antenna(e). Incertain embodiments, the transmitter component may be made up of one ormore coils. As such, the signal transmitter may include a variety ofdifferent transmitters, e.g., electrodes, antennas (e.g., in the form ofwires) coils, etc. In certain embodiments, the signal may be transmittedeither by one or two electrodes or by one or two wires. A two-electrodetransmitter may be a dipole; a one electrode transmitter forms amonopole. In certain embodiments, the transmitter may only require onediode drop of power.

Additional Components

Depending on the particular embodiment, the identifier may include anumber of different additional components. Some components of interestinclude, but are not limited, those reviewed below.

Power Enhancers

Where the activator is a power source that is turned on upon contactwith a target physiological site, in certain embodiments, circuits forenhancing or boosting voltage of the analog circuit voltage rails, maybe provided, e.g., charge pumping circuits, charge doublers, etc. Byincreasing the voltage of certain nodes, improved performance ofcritical functions, such as oscillators, can be achieved.

Power Storage

In certain embodiments, the activation component may include a powerstorage element. For example, a duty cycle configuration may beemployed, e.g., where slow energy production from a battery is stored ina power storage element, e.g., in a capacitor, which then may provide aburst of power that may be deployed to the signal generation component.In certain embodiments, the activation component may include a timingelement which modulates, e.g., delays, delivery of power to the signalgeneration element, e.g., so signals from different compositions, e.g.,pills, that are administered at substantially the same time may beproduced at different times and are therefore distinguishable.

Identifier Fabrication

In certain embodiments of interest, the identifier element includes asemiconductor support component. Any of a variety of different protocolsmay be employed in manufacturing the identifier structures andcomponents thereof. For example, molding, deposition and materialremoval, e.g., planar processing techniques, such asMicro-Electro-Mechanical Systems (MEMS) fabrication techniques,including surface micromachining and bulk micromachining techniques, maybe employed. Deposition techniques that may be employed in certainembodiments of fabricating the structures include, but are not limitedto: electroplating, cathodic arc deposition, plasma spray, sputtering,e-beam evaporation, physical vapor deposition, chemical vapordeposition, plasma enhanced chemical vapor deposition, etc. Materialremoval techniques include, but are not limited to: reactive ionetching, anisotropic chemical etching, isotropic chemical etching,planarization, e.g., via chemical mechanical polishing, laser ablation,electronic discharge machining (EDM), etc. Also of interest arelithographic protocols. Of interest in certain embodiments is the use ofplanar processing protocols, in which structures are built up and/orremoved from a surface or surfaces of an initially planar substrateusing a variety of different material removal and deposition protocolsapplied to the substrate in a sequential manner.

Specific Pill Embodiments

In further describing various embodiments of the compositions of thedisclosure, specific embodiments are now described in greater detail inview of the figures. In the following detailed description, reference ismade to the accompanying drawings, which form a part hereof. In thedrawings, similar symbols and reference characters typically identifysimilar components throughout the several views, unless context dictatesotherwise.

FIG. 1 is a diagrammatic, exemplary representation of a pill/capsuleembodiment of the present disclosure, according to one aspect of thepresent disclosure, in which the composition is configured as an orallyingestible pharmaceutical formulation in the form of a pill or capsule.The stomach 12 of the patient 10 who ingests the composition 14 isshown. This “smart pill” is shown as it has traveled from the mouth 16to inside 18 the patient's stomach. Upon reaching the stomach, thepill/capsule may undergo a dissolving process with both the mechanicalaction of the stomach and the various chemical materials in the stomachfluids, such as hydrochloric acid and other digestive agents.

FIG. 2 is a more detailed view of the pill composition shown in FIG. 1 .FIG. 2 illustrates an identifier 20 disposed inside a pill 14.Identifier 20 is present as an integrated circuit (IC). The backside(bottom) of circuit 20 may be at least partially coated with a firstmetal 21, and a portion of the front (top) of circuit 20 may be coatedwith a different metal 22, allowing circuit 20 to be powered by reverseelectrolysis. Also on the top surface may be two transmitter electrodes23, 24.

When pill 14 is fabricated, the integrated circuit 20 may be surroundedby at least one external layer that may include pharmacologically activeand/or inert materials in any combination. The external layer maydissolve in the stomach through a combination of the mechanical actionof the stomach and the action of various chemical constituents (e.g.,hydrochloric acid) in stomach fluids.

As pill 14 is dissolved, areas of integrated circuit 20 may becomeexposed to the stomach contents, which for present purposes can beregarded as an electrolyte solution. As dissolution of the pill exposesmetal layers 21 and 22 (magnesium metal and copper chloride), power maybe supplied to circuit 20, which may begin to operate and continue tooperate until metal layers 21 and 22 or the circuit itself aresufficiently dissolved by digestive processes and acids to becomenon-functional. Eventually, the remains of the chip are excreted fromthe body.

In an alternative embodiment, the integrated circuit 20 may be attachedto, rather than encapsulated in, the pill 14. For instance, circuit 20might be placed at one end of the pill as the pill is being prepared, ina soluble coating on the surface of the pill, or the like. Inembodiments where circuit 20 is wholly or partially exposed, integratedcircuit 20 may begin to operate sooner after the pill enters the stomachrather than after the pill dissolves.

In one embodiment, circuit 20 may transmit a signal identifying pill 14.The identifier may indicate the type (lisinopril, brand, etc.) and/ordosage of pill 14 and may also provide a lot number, serial number, orsimilar identifying information that would allow particular pills to betraced, e.g., as reviewed above.

FIG. 3 is a detailed depiction of an embodiment of a signal generationelement 30 which labels the pharmaceutical material and is encapsulatedin the center of the composition, according to one aspect of the presentdisclosure. Signal generation element 30 is in the form of ICconstructed from a silicon chip where various functional elements, e.g.,in the form of one or more layers of circuits, may be disposed on asilicon substrate 31. The chip can be fabricated using standardintegrated circuit techniques. An example of such a fabrication approachmay be a 0.5μ CMOS process made available by AMI Semiconductor in Idaho,USA. Shown on the backside of the substrate, the bottom of the chip 31may be metal 1 32 which functions as one battery electrode (magnesiummetal or copper chloride), and on the topside of the chip may be metal 233 which functions as the other battery electrode (copper chloride, ormagnesium metal). Also on the top side of the chip 31 may be electrode 134 and electrode 2 35, which may constitute a pair ofsignal-transmission electrodes.

In some cases, dissolution of the electrodes, and thus extinction of thereporting signal, can provide a secondary indication of the fulldissolution of the pill and incorporated devices.

A potential applied to the silicon may be a positive voltage on the topsurface and a negative voltage on the bottom surface. In this way, thesubstrate may be essentially at the same potential as the cathode, whichcan be the ground reference for the circuits, and the top surface, witha SiO₂ insulation layer, may be coupled to a positive voltage,referenced to that ground on the bottom side.

In certain embodiments, the signal generation element may not includeantennae and instead uses battery components as antennae, such as shownin FIGS. 4A and 4B. In FIG. 4A, signal generation element 30 may includesilicon support layer 31 positioned between metal 1 layer 32 and metal 2layer 33. Also shown is circuitry layer 38. In such embodiments, when aswitch on the chip, e.g., in the circuitry layer, is closed, a currentmay be produced between the two metals of the battery, which is thendetected. In certain embodiments, a membrane larger than the chip, whichdefines a path for the current to travel, may be provided. As shown inFIG. 4B, in certain embodiments, a non-conductive “skirt” membrane orfilm 39 is attached to the chip that increases the length of theconductive current path between metal 1 layer 32 and metal 2 layer 33.As illustrated, the positive and negative ions must travel around thenon-conductive skirt membrane or film 39, increasing the current path.The dipole moment is therefore increased, which increases signalstrength generated by the chip powered by the closed circuit formed bythe current path between the metal 1 layer 32 and the metal 2 layer 33.The non-conductive skirt membrane or film 39 may be composed ofnon-conductive material, such as hydroxypropyl cellulose, or othercompositions of cellulose described herein.

Methods of Making Compositions

The compositions provided herein address a number of intertwinedproblems related to development of functional lisinopril/IEMcompositions such as, but not limited to, those related to the specificactive pharmaceutical ingredient used herein (e.g., long disintegrationtimes, or slow dissolution times), functionality of the IEM (e.g., longtime to activation, low peak mean amplitude of signal, die fall out,mechanical stability of the compositions (e.g., tablet cracking, or poorfriability), and shelf-life stability of the active pharmaceuticalingredient, tablet, or IEM. For example, one should not expect thatcertain carriers described herein are readily interchangeable with otherpharmaceutically acceptable carriers while also addressing, at least,each of the above-noted issues. Similarly, one should not expect thatcertain IEM elements described herein are readily interchangeable withothers while also addressing, at least, each of the above-noted issues.Furthermore, one should not expect that the specific activepharmaceutical ingredient (i.e., lisinopril) described herein is readilyinterchangeable with other active pharmaceutical ingredients while alsoaddressing, at least, each of the above-noted issues.

A variety of manufacturing protocols may be employed to producecompositions according to the present disclosure. In manufacturing thesubject compositions, a signal generation element may be stablyassociated with the pharmaceutical dosage such that the signalgeneration element and the dosage do not separate from each other, atleast until administered to the subject in need thereof, e.g., byingestion. The signal generation element may be stably associated withthe pharmaceutical carrier/lisinopril component of the composition in anumber of different ways.

In some embodiments, where the carrier/lisinopril component is a solidstructure, e.g., such as a tablet or pill, the carrier/lisinoprilcomponent may be produced in a manner that provides a cavity for thesignal generation element. The signal generation element may then beplaced into the cavity and the cavity sealed, e.g., with a biocompatiblematerial, to produce the final composition. For example, in certainembodiments, a tablet may be produced with a die that includes a featurewhich produces a cavity in the resultant compressed tablet. The signalgeneration element may be placed into the cavity and the cavity sealedto produce the final tablet. In a variation of this embodiment, thetablet may be compressed with a removable element, e.g., in the shape ofa rod or other convenient shape. The removable element may then beremoved to produce a cavity in the tablet. The signal generation elementmay be placed into the cavity and the cavity sealed to produce the finaltablet. In another variation of this embodiment, a tablet without anycavity is first produced and then a cavity is produced in the tablet,e.g., by laser drilling. The signal generation element is placed intothe cavity and the cavity sealed to produce the final tablet.

In some embodiments, a tablet may be produced by combining the signalgeneration element with subparts of the tablet, where the subparts maybe pre-made subparts or manufactured sequentially. For example, incertain embodiments tablets may be produced by first making a bottomhalf of the tablet, placing the signal generation element on a locationof the bottom half of the tablet, and then placing top portion of thetablet over the bottom half and signal generation element to produce thefinal desired composition.

In some embodiments, a tablet may be produced around a signal generationelement such that the signal generation element is located inside of theproduced tablet. For example, a signal generation element, which may ormay not be encapsulated in a biocompatible compliant material, e.g.,gelatin (to protect the signal generation element), may be combined withcarrier/lisinopril precursor, e.g., powder, and compressed or moldedinto a tablet in a manner such that the signal generation element islocated at an internal position of the tablet.

The inventors have recognized that it is difficult to combine apharmaceutical compound with an IEM device to manufacture a stablepharmaceutical product with a reasonable shelf life that meets the FDArequirements and still achieve the functions of the IEM device. Forexample, tablets may be manufactured by pressing the pharmaceuticalcompound with a certain pressure, but when an IEM device is combinedwith the pharmaceutical compound to make the tablets, the pressure usedto press the tablets must be carefully tested. Too much pressure wouldlikely damage the IEM device, but if too little pressure is used, themanufactured tablets may not have the desired hardness and otherproperties to meet the FDA requirements. Further, the conditions of themanufacturing process may vary depending on the specific compositionsused, such as the lisinopril, the elements/compositions of the IEMdevice, and the amounts thereof, which may also affect the properties ofthe manufactured pharmaceutical product, such as tablets. The inventorshave surprisingly discovered that the compositions of the presentdisclosure, for example, when manufactured as described in greaterdetail below, may meet the desired requirements while still achievingthe desired functions of the IEM device.

Accordingly, the present disclosure provides a unique composition ofmatter comprising the combination of the IEM electronic circuitrycomprising battery forming materials and specific formulations oflisinopril to confirm the delivery of the specific formulations oflisinopril. The compositions provided herein overcome the unpredictablenature (e.g., impact on functionality, shelf-life, structural stability,chemical stability, etc.) of combining various metals and salts with thespecific formulations of lisinopril to provide an electronic IEMdelivery system that generates its own electrical power from a partialenergy source comprised of dissimilar materials when exposed with thebodily fluids of a patient during the oral administration of thespecific formulations of lisinopril.

Methods of Treatment

In one aspect, provided herein are methods of treating a disease in asubject in need thereof, comprising administering a lisinoprilcomposition provided herein to the subject. In some embodiments, thedisease is hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy. Thus, in some embodiments, providedherein is a method of treating hypertension in a subject in needthereof, comprising administering a lisinopril composition providedherein to the subject. In some embodiments, provided herein is a methodof treating congestive heart failure in a subject in need thereof,comprising administering a lisinopril composition provided herein to thesubject. In some embodiments, provided herein is a method of treatingacute myocardial infarction in a subject in need thereof, comprisingadministering a lisinopril composition provided herein to the subject.In some embodiments, provided herein is a method of treating diabeticnephropathy in a subject in need thereof, comprising administering alisinopril composition provided herein to the subject.

In some embodiments, provided herein is a method of treating a disease(e.g., hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy) in a subject in need thereofcomprising administering an ingestible event marker composition to thesubject, wherein the composition comprises:

1) a granule comprising:

-   -   about 10.3% w/w lisinopril;    -   about 15.5% w/w dicalcium phosphate dihydrate;    -   about 58.6% w/w mannitol (e.g., 180 μm);    -   about 15.5% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow;

2) an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

3) about 0.5% to about 1% w/w magnesium stearate; and

4) about 0% to about 2% w/w croscarmellose sodium; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier magnesiumstearate, and croscarmellose sodium are encapsulated within a capsule(e.g., a gelatin or hydroxypropyl methylcellulose capsule).

In some embodiments, provided herein is a method of treating a disease(e.g., hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy) in a subject in need thereofcomprising administering an ingestible event marker composition to thesubject, wherein the composition comprises:

1) a granule comprising:

-   -   about 10.3% w/w lisinopril;    -   about 15.5% w/w dicalcium phosphate dihydrate;    -   about 58.6% w/w mannitol (e.g., 180 μm);    -   about 15.5% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow;

2) an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

3) about 0.5% w/w magnesium stearate; and

4) about 5% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier magnesiumstearate, and pregelatinized starch are encapsulated within a capsule(e.g., a gelatin or hydroxypropyl methylcellulose capsule).

In some embodiments, provided herein is a method of treating a disease(e.g., hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy) in a subject in need thereofcomprising administering an ingestible event marker composition to thesubject, wherein the composition comprises:

1) a granule comprising:

-   -   about 11.2% w/w lisinopril;    -   about 16.9% w/w dicalcium phosphate dihydrate;    -   about 60.5% w/w mannitol (e.g., 180 μm);    -   about 11.2% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow; and

2) an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

3) about 0.5% w/w magnesium stearate; and

4) about 5 to about 10% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier, magnesiumstearate, and pregelatinized starch are encapsulated within a capsule(e.g., a gelatin or hydroxypropyl methylcellulose capsule).

In some embodiments, provided herein is a method of treating a disease(e.g., hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy) in a subject in need thereofcomprising administering an ingestible event marker composition to thesubject, wherein the composition comprises:

1) a granule comprising:

-   -   about 11.2% w/w lisinopril;    -   about 16.9% w/w dicalcium phosphate dihydrate;    -   about 60.5% w/w mannitol (e.g., 180 μm);    -   about 11.2% w/w pregelatinized starch; and    -   about 0.15% w/w iron oxide yellow; and

2) an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

3) about 0.5% w/w magnesium stearate; and

4) about 5% w/w pregelatinized starch; and

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating, and the granule, identifier, magnesiumstearate, and pregelatinized starch are encapsulated within a capsule(e.g., a gelatin or hydroxypropyl methylcellulose capsule).

In some embodiments, provided herein is a method of treating a disease(e.g., hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy) in a subject in need thereofcomprising administering an ingestible event marker composition to thesubject, wherein the composition comprises:

about 7.3% w/w lisinopril;

about 30.0% w/w dicalcium phosphate dihydrate;

about 24.6% w/w mannitol (e.g., 50 μm);

about 20.0% w/w pregelatinized starch;

about 15.0% w/w microcrystalline cellulose;

about 2.0% w/w croscarmellose sodium;

about 0.15% w/w yellow iron oxide;

about 1.0% w/w magnesium stearate; and

an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating.

In some embodiments, provided herein is a method of treating a disease(e.g., hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy) in a subject in need thereofcomprising administering an ingestible event marker composition to thesubject, wherein the composition comprises:

about 7.3% w/w lisinopril;

about 15.0% w/w dicalcium phosphate dihydrate;

about 24.6% w/w mannitol (e.g., 50 μm);

about 20.0% w/w pregelatinized starch;

about 30.0% w/w microcrystalline cellulose;

about 2.0% w/w croscarmellose sodium;

about 0.15% w/w yellow iron oxide;

about 1.0% w/w magnesium stearate; and

an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating.

In some embodiments, provided herein is a method of treating a disease(e.g., hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy) in a subject in need thereofcomprising administering an ingestible event marker composition to thesubject, wherein the composition comprises:

about 7.3% w/w lisinopril;

about 30.0% w/w dicalcium phosphate dihydrate;

about 24.6% w/w mannitol (e.g., 50 μm);

about 20.0% w/w pregelatinized starch;

about 15.0% w/w microcrystalline cellulose;

about 2.0% w/w croscarmellose sodium;

about 0.15% w/w yellow iron oxide;

about 1.0% w/w magnesium stearate; and

an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein

the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating,

the lisinopril, dicalcium phosphate dihydrate, mannitol (e.g., 50 μm),pregelatinized starch, microcrystalline cellulose, croscarmellosesodium, yellow iron oxide, and identifier are compressed to form aninner compressed tablet, and

the magnesium stearate is compressed as an outer compressed shellencapsulating the inner compressed tablet.

In some embodiments, provided herein is a method of treating a disease(e.g., hypertension, congestive heart failure, acute myocardialinfarction, or diabetic nephropathy) in a subject in need thereofcomprising administering an ingestible event marker composition to thesubject, wherein the composition comprises:

about 7.3% w/w lisinopril;

about 15.0% w/w dicalcium phosphate dihydrate;

about 24.6% w/w mannitol (e.g., 50 μm);

about 20.0% w/w pregelatinized starch;

about 30.0% w/w microcrystalline cellulose;

about 2.0% w/w croscarmellose sodium;

about 0.15% w/w yellow iron oxide;

about 1.0% w/w magnesium stearate; and

an identifier comprising:

-   -   a) an integrated circuit comprising silicon, aluminum, silicon        dioxide, and silicon nitride;    -   b) a wafer comprising titanium, titanium-tungsten, gold,        magnesium, copper (I) chloride, and hydroxypropyl cellulose; and    -   c) a skirt film comprising ethyl cellulose, hydroxypropyl        cellulose, and triethyl citrate;

wherein

the integrated circuit, wafer and skirt film are coated with ahydroxypropyl cellulose coating,

the lisinopril, dicalcium phosphate dihydrate, mannitol (e.g., 50 μm),pregelatinized starch, microcrystalline cellulose, croscarmellosesodium, yellow iron oxide, and identifier are compressed to form aninner compressed tablet, and

the magnesium stearate is compressed as an outer compressed shellencapsulating the inner compressed tablet.

The term “treating” as used herein includes the diagnosis, mitigation,or prevention of progression of a condition or a disease in a subject(e.g., in man or other animals).

EXAMPLES Example 1 Manufacturing of Power Source and IEM

According to one aspect of the present disclosure, a partial powersource may be manufactured as described in detail herein.

A semiconductor substrate may be provided as a chassis which componentsof the IEM are attached to, deposited upon, and/or secured to. Thesubstrate may be made of silicon. The cathode material may be physicallyassociated with the substrate (e.g., on one side). The cathode materialmay be chemically deposited on, evaporated onto, secured to, or built-upon the substrate all of which may be referred to herein as “deposit”with respect to the substrate. The cathode material may be deposited onone side of the substrate. The cathode material may be deposited byphysical vapor deposition, electrodeposition, or plasma deposition,among other protocols. The cathode material may be from about 0.05 toabout 500 μm thick, such as from about 5 to about 100 μm thick. Theshape may be controlled by shadow mask deposition, or photolithographyand etching. Additionally, there may be more than one electricallyunique region on the substrate where the cathode material may bedeposited, as desired.

At a different side, which may be the opposite side to the side wherethe cathode material is deposited, the anode material may be deposited.The different side selected may be the side next to the side selectedfor the cathode material. The scope of the present disclosure is notlimited by the side selected, and the term “different side” can mean anyof the multiple sides that are different from the first selected side.Furthermore, the shape of the deposited material(s) may be anygeometrically suitable shape. The materials are selected such that theymay produce a voltage potential difference when the power source is incontact with conducting liquid, such as body fluids. As indicated abovewith respect to the cathode material, the anode material may bechemically deposited on, evaporated onto, secured to, or built-up on thesubstrate. Also, an adhesion layer may be necessary to help the anodematerial (as well as the cathode material when needed) to adhere to thesubstrate to provide better electrode contact between the substrate andthe electrode material. Typical adhesion layers for the anode materialmay be Au, Ti, TiW, or similar material. The adhesive layer may have athickness from 50 Å to 100 Å and up to 1 μm (e.g., about 50 Å to about 1μm, about 100 Å to about 1 μm, or about 50 Å to about 100 Å). The anodematerial and the adhesion layer may be deposited by physical vapordeposition, electrodeposition or plasma deposition. The anode materialmay be from about 0.05 to about 500 μm thick, such as from about 5 toabout 100 μm thick. However, the scope of the present disclosure is notlimited by the thickness of any of the materials nor by the type ofprocess used to deposit or secure the materials to the substrate.

According to the disclosure set forth, when used with ingestiblelisinopril IEM tablets manufactured as described below, the electrodematerials are magnesium metal and copper chloride (e.g., copper (I)chloride, CuCl, or cuprous chloride). That is, the anode comprisesmagnesium metal, and the cathode comprises copper chloride.

In some embodiments, the power source in each lisinopril IEM tablet,manufactured as described below, may include about 0.9 mg of Si, 0.2 mgof Cu, and 0.01 mg of Mg. There is a thick (about 4-8 um, e.g. about 6μm) layer of gold under the CuCl to increase the surface roughness. Theamounts of the materials may be sufficient for generating enough powerfor the IEM to have a communication time of at least or about 1 minute,e.g., about at least or about 2 minutes, e.g., at least or about 3minutes, e.g., at least or about 4 minutes, e.g., at least or about 5minutes, e.g., at least or about 6 minutes, e.g., at least or about 7minutes, e.g., at least or about 8 minutes, e.g., at least or about 9minutes, e.g., at least or about 10 minutes, e.g., at least or about 15minutes, e.g., at least or about 20 minutes, or a range bounded by anyof these values. A target communication time may be about 1.5 hours. Thepower source in each lisinopril IEM tablet may include at least 0.09 mgof Si, 0.02 mg of Cu, and 0.001 mg of Mg. The greater surface areas theelectrodes may have, the more power and the stronger signals the IEM maygenerate, and at the same time, the more materials the power source mayhave. However, the quantities of the materials used may have to meet therequirements set forth by FDA with respect to the specific elements.Therefore, for example, the maximum amounts of Si, Cu, and Mg,respectively, in each tablet may not exceed the maximum amounts of Si,Cu, and Mg, respectively, as set forth by FDA.

In certain aspects, these two electrode materials may be shielded fromthe surrounding environment by an additional layer of material.Accordingly, when the shield is dissolved and the two dissimilarmaterials (magnesium metal and copper chloride) are exposed to thetarget site, a voltage potential is generated.

Other components of the IEM may be provided as described above.

In some embodiments, the IEM comprises an integrated circuit, a wafer, askirt, and a coating. In some embodiments, the integrated circuitcomprises silicon (Si), aluminum (Al), silicon nitride (Si₃N₄), andsilicon dioxide (SiO₂). In some embodiments, the Al, Si₃N₄, and SiO₂exist in multiple thin layers on the surface of a die body (e.g.,silicon) to form the electrical interconnects of the integrated circuit.In some embodiments, the integrated circuit further comprises at leastone dopant. In some embodiments, the dopant is boron (B). In someembodiments, the IEM comprises the components described in Table 1.

TABLE 1 Exemplary IEM (Ingestible Event Marker) Identifier Composition.Density Area Thickness Fraction Volume Component Source Component (g/cc)(mm{circumflex over ( )}2) (mm) (%) (cc) Mass (g) Integrated silicon2.33 1.06 0.3  96.60% 3.18E−04 7.42E−04 circuit aluminum 2.7 1.06 0.0011  0.40% 1.20E−06 3.10E−06 silicon dioxide 2.2 1.06 0.0083   2.50%8.80E−06 1.94E−05 silicon nitride 3.1 1.06 0.00102   0.40% 1.10E−063.40E−06 integrated circuit  19.50% 7.68E−04 total mass Wafer titanium4.54 1.06 0.0002   0.80% 2.12E−07 9.63E−07 titanium-tungsten 14.44 0.810.00032   2.40% 2.05E−07 3.00E−06 gold 19.32 0.81 0.006  60.20% 3.80E−067.42E−05 magnesium 1.74 1.06 0.008  12.00% 8.50E−06 1.48E−05 copper (I)chloride 4.14 0.74 0.0076  18.90% 5.60E−06 2.33E−05 hydroxypropyl 1.11.06 0.006   5.70% 6.40E−06 7.00E−06 cellulose solvent-ethanol (no tracedetectable) wafer total mass   3.10% 1.23E−04 Skirt film ethyl cellulose1.1 8.62 0.3  49.60% 1.30E−03 1.40E−03 hydroxypropyl 1.1 8.62 0.3 30.20% 7.76E−04 8.53E−04 cellulose triethyl citrate 1.1 8.62 0.3 20.20% 5.17E−04 5.69E−04 solvent-none (extruded) skirt film total mass 71.50% 2.82E−03 IEM hydroxypropyl 1.1 7.07 0.03 100.00% 2.12E−042.33E−04 identifier- cellulose level solvent-ethanol coating (no tracedetectable) IEM identifier-  5.90% 2.33E−04 level coating total massTotal IEM 100.00% 3.95E−03 identifier mass

Example 2 Manufacturing of Lisinopril IEM Tablets

According to one aspect of the present disclosure, lisinopril IEMtablets may be manufactured using the IEM manufactured in Example 1 andusing the processes described in U.S. Pat. No. 8,784,308. Anillustration process is described below.

In some embodiments, the lisinopril IEM tablets comprise lisinopril andthe components described in Table 1.

As in FIGS. 5-7 , a tablet press 50 is shown. The press 50 may rotate ina counter-clockwise direction as shown. The press 50 may include diecavity or punch cavity 52 and an ejection tray 54. Starting at positionA, as shown, the pharmaceutical product, lisinopril, may be deposited inthe cavity 52. The press 50 may rotate to position B, which may bepositioned below a transfer wheel 60. The wheel 60 may include severalopenings 62. As the wheel 60 passes position C, each opening 62 may passunder a feeder 70, as shown in FIG. 7 .

The feeder 70 may contain marker devices 200. The device 200 may be anIEM that is activated upon contact with a conducting fluid, manufacturedas described above in Example 1. The scope of the present disclosure isnot limited by the environment or type of the conducting fluid. Onceingested, the device 200 may come into contact with a conducting fluid,such as stomach fluids, and the device 200 may be activated. Referringto the instance where the device 200 is used with the product that isingested by the living organism, when the product that includes thedevice 200 is taken or ingested, the device 200 may come into contactwith the conducting liquid of the body, a voltage potential may becreated, and the device 200 may be activated. A portion of the powersource may be provided by the device 200, such as the electrodematerials as described above, while another portion of the power sourcemay be provided by the conducting fluid.

Referring again to FIGS. 5 and 6 , each time an opening 62 passes underthe feeder 70, one of the devices 200 may be dropped into the opening 62directly under the feeder 70. As shown in FIG. 6 , a force “F” is shownto assist the movement of the device 200 from the feeder 70 into theopening 62. The force may be provided by the use of a vacuum through asuction tube 68. In accordance with other aspects of the presentdisclosure, the force may be provided by a spring, an air burst, or anejection pin in addition to gravity. The wheel 60 may rotate to positionB. At position B, the device 200 located in the opening 62 may bedropped into the cavity 52 of the press 50. The press 50 may rotate tothe position D where additional pharmaceutical product may be depositedinto the cavity 52 on top of the device 200. The press 50 may continueto move in the counter-clockwise direction and at position E, thecontent of the cavity 52 may be pressed under high pressure to form atablet with the device 200 inside. The completed tablet may be ejectedand moved to a collection point through the ejection tray 54 for furtherprocessing, such as coating layers as needed.

Referring now to FIG. 8 , a feeder assembly 72 is shown as alternativeembodiment and in accordance with another aspect of the presentdisclosure. The feeder assembly 72 can be used in place of the feeder 70of the FIG. 5 . The feeder assembly 72 may include a plurality ofsupporting fingers 74 that hold each device 200 in position. The fingers74 may be connected to a belt 76. The fingers 74 may lower the device200 toward the wheel 60 of FIG. 5 . When the fingers 74 may reach thelower portion near the wheel 60, the fingers 74 may move apart and dropthe device 200 into the opening 62 of the wheel 60.

Referring now to FIG. 9A and FIG. 9B, in accordance with another aspectof the present disclosure, the feeder assembly 72 may include an ejector73 with a spring 75. As the opening 62 moves under the feeder assembly72, the ejector 73 may push the device 200 into the opening 62 of thewheel 60.

Example 3 Impact of Core and Mantle on Mechanical Properties andAppearance

This experiment examines the effect of various parameters on theperformance of the core, appearance of the core, in particular theformation of stress fractures, and sensor (e.g., identifier) performanceof the digimed tablet. Various combinations of mannitol:dicalciumphosphate:magnesium stearate (88:10:2), lactose monohydrate:magnesiumstearate (98:2), microcrystalline cellulose (avicel PH102 or PH112), andmagnesium stearate were compressed into tablets (5.2 mm diameter and 2.0mm thick, or 6.5 mm diameter and 2.0 mm thick; shallow-concave tablets)comprising a sensor. The tablets were either a core, or a core with anouter coating. The properties of the tablets were assessed immediately(T zero), 24 hours, 72 hours, 7 days, 15 days, and 30 dayspost-compression while being stored at 25° C./60% RH and 40° C./75% RHopen stress conditions (e.g., an open container).

The following attributes of the tablets were assessed: appearance,weight, thickness, diameter, tensile strength, and moisture. The corethat showed the least issues with regard to appearance when studiedunder 25° C./60% RH and 40° C./75% RH for up to 14 days was a lactosebased core. When lactose was combined with either a plastic (Avicel) oranother brittle mantle (lactose or Mannitol/DCP), no cracking wasobserved.

The mannitol/DCP cores showed no cracking at 25° C./60% RH but crackingat 40° C./75% RH when combined with lactose or Avicel mantle. Amannitol/DCP mantle combined with a mannitol/DCP core had a lowincidence of cracking in both conditions.

An Avicel core combined with a lactose mantle gave rise to significantcracking in both 25° C./60% RH and 40° C./75% RH. An avicel corecombined with mannitol/DCP had a mixed result in that the smaller core5220 saw significant cracking in both conditions whereas the 6520 sizecore showed no cracking at either condition. An avicel core and avicelmantle showed no cracking under 25° C./60% RH but some degree ofcracking at 40° C./75% RH.

Tablets were placed in a sensor activation media and sensor performancewas assessed. The results showed that mannitol:dicalciumphosphate:magnesium stearate cores and lactose:magnesium stearate coresdo not pass sensor performance criteria (long activation time [mannitolonly] and low peak mean amplitude).

Example 4 Influence of Disintegrant on Sensor Performance in VariousCore Formulations

This experiment examines the effect of different types of disintegrantand their concentration within the core formulation on sensorperformance. Various excipient filler combinations were combined withdifferent disintegrants. The superdisintegarnts; croscarmellose sodium,sodium starch glycolate and crospovidone were individually combined atthe 2% concentration level with the following core blend formulations;mannitol:dicalcium phosphate anhydrous:magnesium stearate (86.5:10:1.5),microcrystalline cellulose:magnesium stearate (97.0:1.0), lactosemonohydrate:magnesium stearate (96.5:1.5). Pregelatinized starch at the10% level was evaluated with the following core formulations;mannitol:dicalcium phosphate anhydrous:magnesium stearate(79.75:10:0.25), microcrystalline cellulose:magnesium stearate(89.75:0.25), lactose monohydrate:magnesium stearate (89.75:0.25).Microcrystalline cellulose at the 15% level was investigated with thefollowing core formulations; mannitol:dicalcium phosphateanhydrous:magnesium stearate (73.5:10:1.5), lactosemonohydrate:magnesium stearate (83.5:1.5). The tablets were allcompressed using round, 5.2 mm diameter shallow concave tooling to amean thickness of 2 mm.

The tablets were all assessed for sensor performance by placing them insensor media. The results showed that the mannitol:dicalcium phosphateanhydrous disintegrant combinations and the microcrystalline cellulosedisintegrant combinations studied all pass the sensor performancecriteria at the disintegrant concentrations used. The lactosedisintegrant combinations did pass the sensor performance criteriahowever this was associated with a high degree of variability andprolonged activation times.

Example 5 Disintegrant Level Optimization in Various Core Formulations

This experiment examines the effect of type and amount of disintegrantincluded in lactose-based formulations; lactosemonohydrate:croscarmellose sodium:magnesium stearate (94.5:4.0;1.5),lactose monohydrate:sodium starch glycolate:magnesium stearate(90.5:8.0;1.5), lactose monohydrate:crospovidone:magnesium stearate(93.5:5.0;1.5), lactose monohydrate:pregelatinized starch:magnesiumstearate (79.5:20.0;0.5). The tablets were all assessed for sensorperformance by placing them in sensor media. The increase in the amountof disintegrant improved the sensor performance attributes of peak meanamplitude, counts and time to activation, whilst also reducing theoverall variability seen with the lactose monohydrate based cores.

Example 6 Die Fall Out (DFO) Propensity of Optimized Core Formulations

This experiment examines the sensor performance and the propensity forDie Fall Out (DFO) of optimized cores within a slowly dissolving (e.g.metformin) mantle. The following cores were compressed using round, 5.2mm diameter shallow concave tooling; mannitol:dicalcium phosphateanhydrous:croscarmellose sodium:magnesium stearate (86.5:10:2.0:1.5),mannitol:dicalcium phosphate anhydrous:sodium starch glycolate:magnesiumstearate (86.5:10:2.0:1.5), mannitol:dicalcium phosphate:starch1500:magnesium stearate (79.75:10:10:0.25), mannitol:dicalcium phosphateanhydrous:microcrystalline cellulose:magnesium stearate(73.5:10:15:1.5), microcrystalline cellulose (PH102):croscarmellosesodium:magnesium stearate (97.0:2.0:1.5), microcrystalline cellulose(PH102):sodium starch glycolate:magnesium stearate (97.0:2.0:1.5),microcrystalline cellulose (PH102):starch 1500:magnesium stearate(89.75:10:0.25), lactose monohydrate:croscarmellose sodium:magnesiumstearate (94.5:4.0;1.5), lactose monohydrate:sodium starchglycolate:magnesium stearate (90.5:8.0;1.5), lactose monohydrate:starch1500:magnesium stearate (79.75:20.0;0.25). The cores were thencompressed inside the metformin mantle using round 10.0 mm diametertooling. The tablets were all assessed for sensor performance by placingthem in sensor media. All cores showed zero DFO except for themicrocrystalline cellulose:croscarmellose sodium:magnesium stearate corewhich showed 4%.

Example 7 Impact of Core Shape on Die Fall Out (DFO)

This experiment investigated whether the shape of the tablet couldaffect the propensity for DFO observed with different core formulations.The following cores were compressed into flat faced and shallow concaveshapes using round 5.2 mm diameter shallow concave and round 5.2 mmdiameter flat beveled edge tooling. Microcrystallinecellulose:croscarmellose sodium:magnesium stearate (97:2:1), lactosemonohydrate:croscarmellose sodium:magnesium stearate (94.5:4:1.5),mannitol:dicalcium phosphate anhydrous:croscarmellose sodium:magnesiumstearate (86.5:10:2:1.5). The cores were then compressed inside ametformin mantle using round 10.0 mm diameter tooling. The resultanttablets were all assessed for sensor performance, in particular DFO byplacing them in sensor media. The lactose and mannitol:dicalciumphosphate anhydrous based cores showed no DFO in combination with thecroscarmellose sodium disintegrant for either tablet shape; flat facedbeveled edge and shallow concave. The combination of microcrystallinecellulose and croscarmellose sodium showed DFO for both tooling shapeswith the FFBE shape having a higher incidence of 22% compared to 7% forthe shallow concave. The following cores were compressed using 5.2 mmflat faced beveled edge tooling and then compressed inside a metforminmantle using round 10.0 mm diameter tooling before being assessed forsensor performance, in particular DFO by placing them in sensor media.Microcrystalline cellulose:sodium starch glycolate:magnesium stearate(97:2:1), Microcrystalline cellulose:starch 1500:magnesium stearate(89.75:10:0.25), lactose monohydrate:sodium starch glycolate:magnesiumstearate (90.5:8:1.5), lactose monohydrate:starch 1500:magnesiumstearate (79.75:20:0.25), mannitol:dicalcium phosphate anhydrous:sodiumstarch glycolate:magnesium stearate (86.5:10:2:1.5), mannitol:dicalciumphosphate anhydrous:starch 1500:magnesium stearate (79.75:10:0.25),mannitol:dicalcium phosphate anhydrous:microcrystallinecellulose:magnesium stearate (73.5:10:15:1.5). None of the cores testedshowed DFO.

Example 8 Impact of Compaction Pressure on Tensile Strength, SolidFraction, and Sensor Performance of Core Formulations

Core tablet formulations were compressed over a range of compactionpressures in order to assess the impact on sensor performance.Mannitol:dicalcium phosphate anhydrous:microcrystallinecellulose:magnesium stearate (73.5:10:15:1.5), lactosemonohydrate:croscarmellose sodium:magnesium stearate (94.5:4:1.5) andmicrocrystalline cellulose:croscarmellose sodium:magnesium stearate(97:2:1) were all compressed using round 5.2 mm diameter flat facedbeveled edge tooling. The sensor performance of the cores was assessedby placing them in sensor media. The results showed that as thecompaction pressure increased the time to activation increased with themost significant increases seen with the lactose based core. The othersensor attributes peak mean amplitude and counts passed performancecriteria at all compaction pressures.

Mannitol:dicalcium phosphate anhydrous:microcrystallinecellulose:magnesium stearate (73.5:10:15:1.5), compressed using acompaction pressure of 209 N/mm², lactose monohydrate:croscarmellosesodium:magnesium stearate (94.5:4:1.5) compressed using a compactionpressure of 209 N/mm² and microcrystalline cellulose:croscarmellosesodium:magnesium stearate (97:2:1) compressed using a compactionpressure of 168 N/mm² were compressed inside two different lisinoprilmantles (A5 and B5 as per Table 3).

The resultant lisinopril SP tablets for both the lisinopril A5 and B5formulations were assessed for appearance, sensor performance anddissolution. No major cracks were observed for either formulation as aresult of storage in an open container in 25° C./60% RH for up to 7days. The dissolution in 900 mL of 0.1N HCl (50 rpm, paddle method)showed that the B series lisinopril SP tablet released the drug muchfaster than the A series and so more closely matched the ReferenceProduct. The sensor performance was assessed in sensor media and showedthat the for the A and B Lisinopril products no DFO was observed withany of the cores investigated. Lisinopril SP tablet made with the Bseries had much better sensor performance attributes in terms ofactivation time, peak mean amplitude and counts than the A series.

Example 9 Impact of Optimized Core Formulations on Tensile Strength,Friability, Sensor Performance, and Die Fall Out (DFO)

This experiment investigated alternate core formulations which wereoptimized for compaction properties. The effect of lubrication time onthe tensile strength, friability and sensor performance (peak meanamplitude and counts) was assessed. Table 2 below shows the coreformulations studied.

TABLE 2 Primary Filler Secondary Filler Tertiary Filler DisintegrantLubricant Cores (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) Core #1 89.5%10% Dibasic None None 0.5% microcrystalline calcium phosphate Magnesiumcellulose anhydrous stearate Core #2 87.5% 10% Dibasic None 2% SodiumStarch microcrystalline calcium phosphate Glycolate cellulose anhydrousCore #3 67.5% 30% Mannitol None 2% Croscarmellose microcrystallineSodium cellulose Core #4 57.5% Mannitol 10% Dibasic 30% 2%Croscarmellose calcium phosphate microcrystalline Sodium anhydrouscellulose Core #5 67.5% Mannitol 30% None 2% Croscarmellosemicrocrystalline Sodium cellulose Core #6 65.5% Lactose 30% None 4%Croscarmellose microcrystalline Sodium cellulose Core #7 84% 10% Dibasic1.5% Silicon 4% Croscarmellose (control) microcrystalline calciumphosphate Dioxide Sodium cellulose anhydrous Core #8 98% None 1.5%Silicon None microcrystalline Dioxide cellulose Core #9 66% 30% Mannitol1.5% Silicon 2% Croscarmellose microcrystalline Dioxide Sodium cellulose

Tablet cores were compressed using round 5.2 mm diameter flat facedbeveled edge tooling.

Cores 1, 2 and 3 which have the majority of the formulation based onmicrocrystalline cellulose all showed sensitivity to lubrication time inthat the tensile strength of the resultant tablets after prolongedmixing showed a decrease. Core 9 however although similar to core 3,appeared to overcome the tensile strength lubricant sensitivity issue bythe addition of silicon dioxide to the formulation.

Core 8 showed inferior sensor performance compared to the other corestested.

The tensile strength of cores 4 and 5 was not sensitive to the extendedlubrication times and both showed good sensor performance in sensormedia.

The tensile strength of core 6 showed some sensitivity to lubricationtime in that the prolonged mixing time had a negative effect, tworevised formulations were therefore evaluated. One had the addition of1.5% silicon dioxide and the other saw the removal of themicrocrystalline cellulose component to give the following formulations;lactose monohydrate:microcrystalline cellulose:silicondioxide:croscarmellose sodium:magnesium stearate (64:30:1.5:4:0.5) andlactose monohydrate:croscarmellose sodium:magnesium stearate(95.5:4:0.5). Cores were compressed using round 5.2 mm diameter flatfaced beveled edge tooling. Both formulations no longer demonstratedsensitivity to lubrication time in terms of a negative effect on tensilestrength.

Core 5 (mannitol:dicalcium phosphate anhydrous:croscarmellosesodium:magnesium stearate (67.5:30:2:0.5)), two lactose based cores,lactose monohydrate:microcrystalline cellulose:silicondioxide:croscarmellose sodium:magnesium stearate (64:30:1.5:4:0.5) andlactose monohydrate:croscarmellose sodium:magnesium stearate(95.5:4:0.5) and core 9 (microcrystalline cellulose:mannitol:silicondioxide:croscarmellose sodium:magnesium stearate (66:30:1.5:2:0.5) wereall compressed using round 5.2 mm diameter flat faced beveled edgetooling and then compressed inside the metformin mantle using round 10.0mm diameter tooling to assess the propensity for DFO in sensor media.Both core 5 and the lactose monohydrate:microcrystallinecellulose:silicon dioxide:croscarmellose sodium:magnesium stearate(64:30:1.5:4:0.5) core showed a low incidence of DFO 8% and 3%respectively. None of the other cores showed any DFO.

Example 10 Exemplary Compositions

Table 3 shows exemplary compositions provided herein and theircorresponding physical, mechanical, and electrical characteristics. Eachof the formulations of Table 3 includes an IEM identifier. Table 4 showsexemplary compositions provided herein, which may be in SP TAB, IEM TAB,or SP CAP form.

TABLE 3 Exemplary formulations. IEM- Formulation Component (% w/w)identifier B5 A5 A5 Dose Form Sensor alone SP TAB SP TAB SP TABIntragranular lisinopril — 7.30% 10.00% 10.00% dicalcium — 30.00% 15.00%15.00% phosphate, dihydrate dicalcium — — — — phosphate mannitol —24.60% 53.85% 53.85% (50 um) mannitol — — — — (180 um) pregelatinized —20.00% 10.00% 10.00% starch microcrystalline — 15.00% — — cellulosecroscarmellose — 2.00% — — sodium yellow iron — 0.15% 0.15% 0.15% oxideFD&C yellow — — — — #6 Extra- pregelatinized — — 10.00% 10.00% granularstarch magnesium — 1.00% 1.00% 1.00% stearate croscarmellose — — — —sodium Core Blend — SP1 Mannitol/ Lactose/ dicalcium croscarmellosephosphate/ sodium microcrystalline cellulose Bulk density NA 0.68 0.660.66 (g/mL) Tapped NA 0.85 0.75 0.75 density (g/mL) Appearance - NA YesYes No cracks? (sensor pill tablet includes IEM- identifier)Appearance - NA none NA NA cracks? (IEM- identifier not in tablet)Activation 42 ± 13 499 745 ± 107 944 ± 144 time (s) Peak Mean 189 ± 32 123 155 ± 49  149 ± 50  Amplitude Signal counts 99 ± 12 93 164 ± 33  127± 53  Median 12760 ± 90   NA NA NA Frequency Minimum NA NA 492 685disintegration time (s) Maximum NA NA 587 735 disintegration time (s)Hardness NA 13.7 11.2 15.6 (kP) Compaction NA 122 227 227 pressure(N/mm{circumflex over ( )}2) Tensile NA 0.49 1.42 1.92 Strength(N/mm{circumflex over ( )}2) Friability NA Pass Pass Pass OverallAcceptable Mechanical Long activation Long activation Performancecracking Formulation Component (% w/w) A5 B5 B5 B5 Dose form SP TAB SPTAB SP TAB SP TAB Intragranular lisinopril 10.00% 7.30% 7.30% 7.30%dicalcium phosphate, 15.00% 30.00% 30.00% 30.00% dihydrate dicalciumphosphate — — — — mannitol (50 um) 53.85% 24.60% 24.60% 24.60% mannitol(180 um) — — — — pregelatinized starch 10.00% 20.00% 20.00% 20.00%microcrystaline — 15.00% 15.00% 15.00% cellulose croscarmellose — 2.00%2.00% 2.00% sodium yellow iron oxide 0.15% 0.15% 0.15% 0.15% FD&C yellow#6 — — — — Extragranular pregelatinized starch 10.00% — — — magnesiumstearate 1.00% 1.00% 1.00% 1.00% croscarmellose — — — — sodiumPolyvinylpyrrolidone — — — — Core Blend Main filler Avicel/ Mannitol/Lactose/ Avicel/ AcDiSol DCP/ AcDiSol AcDiSol Avicel Bulk density 0.660.68 0.68 0.68 (g/mL) Tapped 0.75 0.74 0.74 0.74 density (g/mL)Appearance - No Yes No Yes cracks? (sensor pill tablet includes IEM-identifier) Appearance - NA NA NA NA cracks? (IEM- identifier not intablet) Activation 925 ± 116 219 ± 52 341 ± 56  280 ± 46  time (s) PeakMean 185 ± 37  180 ± 44  197 ± 33  234 ± 27  Amplitude Signal counts 106± 29  157 ± 31  130 ± 36  93 ± 18 Median Frequency Minimum 638 59 62 63disintegration time (s) Maximum 714 90 85 78 disintegration time (s)Hardness 10.8 13.2 10.4 9.7 (kP) Compaction 227 NA NA NA pressure(N/mm{circumflex over ( )}2) Tensile 1.32 NA NA NA Strength(N/mm{circumflex over ( )}2) Friability Pass Pass Pass Pass Overall LongMinor Acceptable Minor Performance activation cracking crackingFormulation Component (% w/w) A4 A4 + AcDiSol A4 + Starch A5 + StarchDose form IEM TAB IEM TAB IEM TAB IEM TAB Intragranular lisinopril10.21% 9.69% 9.18% 10.00% dicalcium phosphate, 15.31% 14.53% 13.76%15.00% dihydrate dicalcium phosphate — — — — mannitol (50 um) — — — —mannitol (180 um) 58.02% 55.09% 52.16% 53.85% pregelatinized starch15.31% 14.53% 13.76% 10.00% microcrystalline — — — — cellulosecroscarmellose — — — — sodium yellow iron oxide 0.16% 0.15% 0.14% 0.15%FD&C yellow #6 — — — — Extragranular pregelatinized starch — — 10.00%10.00% magnesium stearate 1.00% 1.00% 1.00% 1.00% croscarmellose — 5.00%— — sodium polyvinylpyrrolidone — — — — Core Blend Main filler not notnot not applicable applicable applicable applicable Bulk density 0.660.66 0.66 0.69 (g/mL) Tapped 0.78 0.78 0.78 0.78 density (g/mL)Appearance - None None None None cracks? (sensor pill tablet includesIEM- identifier) Appearance - NA NA NA NA cracks? (IEM- identifier notin tablet) Activation 1028 826 879 641 time (s) Peak Mean 183 185 53 205Amplitude (uV) Signal counts NA 55 NA 127 Median 12659 12760 12427 12723Frequency Minimum NA NA 600 240 disintegration time (s) Maximum NA NA900 540 disintegration time (s) Hardness 11.7 10.2 8.1 4.3 (kP)Compaction 113 113 113 345 pressure (N/mm{circumflex over ( )}2) Tensile1.58 1.36 1.00 1.24 Strength (N/mm{circumflex over ( )}2) Friability NANA Pass Minor edge Overall Long Long Long Borderline Performanceactivation activation activation mechanical Formulation Component (%w/w) A6a A6b B5 B6 Dose form IEM TAB IEM TAB IEM TAB IEM TABIntragranular lisinopril 18.18% 18.18% 7.27% 10.00% dicalcium phosphate,13.18% 14.32% 30.00% 28.00% dihydrate dicalcium phosphate — — — —mannitol (50 um) 47.50% 51.36% 24.58% 22.85% mannitol (180 um) — — — —pregelatinized starch 10.00% 5.00% 20.00% 20.00% microcrystalline — —15.00% 16.00% cellulose croscarmellose — — 2.00% 2.00% sodium yellowiron oxide 0.14% 0.14% 0.15% 0.15% FD&C yellow #6 — — — — Extragranularpregelatinized starch 10.00% 10.00% — — magnesium stearate 1.00% 1.00%1.00% 1.00% croscarmellose — — — — sodium Polyvinylpyrrolidone — — — —Core Blend Main filler not not not not applicable applicable applicableapplicable Bulk density 0.67 0.63 0.68 0.65 (g/mL) Tapped 0.76 0.82 0.740.75 density (g/mL) Appearance - None None None None cracks? (sensorpill tablet includes IEM- identifier) Appearance - NA NA NA NA cracks?(IEM- identifier not in tablet) Activation 625 572 272 500 time (s) PeakMean 182 188 213 198 Amplitude Signal counts 129 139 125 116 Median12804 12826 12679 12851 Frequency Minimum 180 240 60 120 disintegrationtime (s) Maximum 660 540 240 180 disintegration time (s) Hardness 9.08.6 9.71 11.51 (kP) Compaction 223 223 118 170 pressure (N/mm{circumflexover ( )}2) Tensile 2.11 2.07 0.48 1.05 Strength (N/mm{circumflex over( )}2) Friability Pass Pass Pass Pass Overall Acceptable AcceptableAcceptable Acceptable Performance Formulation Component (% w/w) A4a A4bA4c A4d Dose Form SP CAP SP CAP SP CAP SP CAP Intragranular lisinopril10.26% 10.16% 10.05% 10.10% dicalcium 15.38% 15.23% 15.07% 15.15%phosphate, dihydrate dicalcium — — — — phosphate mannitol (50 um) — — —— mannitol (180 um) 58.32% 57.73% 57.14% 57.44% pregelatinized 15.38%15.23% 15.07% 15.15% starch microcrystalline — — — — cellulosecroscarmellose — — — — sodium yellow iron oxide 0.15% 0.15% 0.15% 0.15%FD&C yellow #6 — — — — Extragranular pregelatinized — — — — starchmagnesium stearate 0.50% 0.50% 0.50% 1.00% croscarmellose — 1.00% 2.00%1.00% sodium Bulk density NA NA NA NA (g/mL) Tapped NA NA NA NA density(g/mL) Appearance - not not not not cracks? applicable applicableapplicable applicable (sensor pill tablet includes IEM- identifier)Appearance - not not not not cracks? applicable applicable applicableapplicable (IEM- identifier not in tablet) Activation 169 ± 48  173 ±31  187 ± 42  198 ± 54  time (s) Peak Mean 167 ± 27  168 ± 25  178 ± 27 176 ± 31  Amplitude Signal counts 78 ± 10 80 ± 10 78 ± 12 77 ± 12 Median12669 ± 78   12673 ± 83   12692 ± 61   12679 ± 69   Frequency Minimum105 75 97 71 disintegration time (s) Maximum 333 263 313 261disintegration time (s) Hardness not not not not (kP) applicableapplicable applicable applicable Compaction not not not not pressureapplicable applicable applicable applicable (N/mm{circumflex over ( )}2)Tensile not not not not Strength applicable applicable applicableapplicable (N/mm{circumflex over ( )}2) Friability not not not notapplicable applicable applicable applicable Overall AcceptableAcceptable Acceptable Acceptable Performance Formulation Component (%w/w) A4e A4f A5a A5b Dose form SP CAP SP CAP SP CAP SP CAP Intragranularlisinopril 10.00% 9.74% 10.62% 10.06% dicalcium 15.00% 14.61% 15.92%15.08% phosphate, dihydrate dicalcium — — — — phosphate mannitol (50 um)— — — — mannitol (180 um) 56.85% 55.39% 57.18% 54.16% pregelatinized15.00% 14.61% 10.62% 10.06% starch microcrystalline — — — — cellulosecroscarmellose — — — — sodium yellow iron oxide 0.15% 0.14% 0.14% 0.13%FD&C yellow #6 — — — — Extragranular pregelatinized 5.00% 5.00% 10.00%starch magnesium stearate 1.00% 0.50% 0.50% 0.50% croscarmellose 2.00% —— — sodium Bulk density 0.66 0.66 0.66 0.66 (g/mL)* Tapped 0.79 0.790.75 0.75 density (g/mL)* Appearance - not not not not cracks?applicable applicable applicable applicable (sensor pill tablet includesIEM- identifier) Appearance - not not not not cracks? applicableapplicable applicable applicable (IEM- identifier not in tablet)Activation 193 ± 41  156 ± 38  168 ± 37  209 ± 50  time (s) Peak Mean180 ± 24  187 ± 35  183 ± 33  178 ± 22  Amplitude Signal counts 75 ± 1073 ± 10 115 ± 14 72 ± 23 Median 12696 ± 81   12672 ± 72   12942 ± 82 12685 ± 75   Frequency Minimum 83 NA NA NA disintegration time (s)Maximum 363 NA NA NA disintegration time (s) Hardness not not not not(kP) applicable applicable applicable applicable Compaction not not notnot pressure applicable applicable applicable applicable(N/mm{circumflex over ( )}2) Tensile not not not not Strength applicableapplicable applicable applicable (N/mm{circumflex over ( )}2) Friabilitynot not not not applicable applicable applicable applicable OverallAcceptable Acceptable Acceptable Acceptable Performance *Note: densitiesbased on intragranular components only. NA = Not Available.

TABLE 4 Exemplary formulations. B6 (F) B6 (P) B7 (P) A6-a (P) A6-b (F)Formulation Dose Total Dose Total Dose Total Dose Total Dose TotalComponents (mg) % w/w (mg) % w/w (mg) % w/w (mg) % w/w (mg) % w/wLisinopril API 40 7.27 40 10 10 5 40 18.18 40 18.18 Dicalcium 82.5 15112 28 61 30.5 29 13.18 31.5 14.32 Phosphate Mannitol 135.18 24.58 91.422.85 50.7 25.35 104.5 47.5 113 51.36 Pregelatinized 110 20 80 20 40 2022 10 11 5 Starch Microcrystalline 165 30 64 16 32 16 0 0 0 0 CelluloseCroscarmellose 11 2 8 2 4 2 0 0 0 0 Sodium Iron Oxide 0.83 0.15 0.6 0.150.3 0.15 0.3 0.14 0.3 0.14 FD&C yellow 0 0 0 0 #6 Pregelatinized 0 0 0 00 0 22 10 22 10 Starch (extra- granular) Magnesium 5.5 1 4 1 2 1 2.2 12.2 1 Stearate (extra- granular) Total (mantle) 550 100 400 100 200 100220 100 220 100

Example 11 Chemical Stability Analysis

Assay and related substances: samples and standards were prepared in20:80 v/v methanol:water at a nominal lisinopril concentration of 0.4mg/mL and a 5 μL aliquot analyzed by high performance liquidchromatography (HPLC) using the following conditions:

-   -   Column: HALO C8, 3.0 mm×75 mm, 2.7 μm (Advanced Materials        Technology Inc., Wilmington, Del., USA);    -   Mobile phase: isocratic; 81:19 v/v water:acetonitrile containing        0.1% v/v trifluoroacetic acid;    -   Mobile phase flow rate: 0.8 mL/min;    -   Column temperature: 15° C.; and    -   Detector: ultraviolet detection at 215 nm.

Dissolution: samples were tested using USP II (Paddle) dissolutionapparatus using 500 mL of 0.01N hydrochloric acid at 37° C. asdissolution medium and a rotational speed of 75 r.p.m. At each specifiedtime point (5 min, 10 min, 15 min and 30 min), 1.5 mL of sample wasfiltered and analyzed using the same HPLC conditions as for assay andrelated substances.

The stability of lisinopril in certain of the compositions providedherein was assessed. The dissolution rate of lisinopril in certain ofthe compositions provided herein was also assessed. Lisinopril is knownto degrade to(2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxo-6,7,8,8a-tetrahydro-3H-pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoicacid. It has been discovered that the compositions provided hereincomprise less than about 0.30%(2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxo-6,7,8,8a-tetrahydro-3H-pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoicacid (diketopiperazine (DKP) impurity) after at least six months ofstorage.

Table 5a describes the formulations used in Table 5b and Table 5c, whichshow percentage of dissolution of certain of the SP TAB lisinoprilcompositions provided herein at time zero (initial preparation of thecomposition) and six months after the initial preparation of thecompositions. Table 6 (lisinopril) and Table 7 (DKP impurity) show theresults of chemical stability analysis of the SP TAB lisinoprilcompositions of Tables 5b-c at time zero and six months. Although otherlisinopril degradation impurities are known, only the DKP impurity wasdetected.

Table 8a describes the formulations used in Table 8b, which showspercentage of dissolution of certain of the IEM TAB lisinoprilcompositions provided herein at time zero (initial preparation of thecomposition) and six months after the initial preparation of thecompositions. Table 9 (lisinopril) and Table 10 (diketopiperazineimpurity) show the results of chemical stability analysis of the IEM TABlisinopril compositions of Tables 8b at time zero and six months.Although other lisinopril degradation impurities are known, only the DKPimpurity was detected.

TABLE 5a Formulations of Table 5b and Table 5c. SP Strength DesiccantReference Formulation Core (mg lisinopril) Mass (g) A6a-9-40-1 A6a with9 40 1 A6a-9-40-3 10% starch 9 40 3 A6a-5B-40-1 5B 40 1 A6a-5B-40-3 5B40 3 B7-5B-10-2 B7 5B 10 2 B7-9-10-2 9 10 2 B6-5B-40-2 B6 5B 40 2B6-5B-40-4 5B 40 4

TABLE 5b Dissolution of selected SP TAB formulations. Mean Result (%dissolved) (Range shown in brackets) Time A6a-9-40-1 A6a-9-40-3A6a-5B-40-1 A6a-5B-40-3 Point (min) Initial 6 months Initial 6 monthsInitial 6 months Initial 6 months 5 84.6 92.4 84.6 87.8 89.8 87.3 89.893.4 (73.6-91.2) (84.6- (73.6- (60.9- (81.7- (82.2- (81.7- (86.1- 97.2)91.2) 98.5) 101.0) 93.3) 101.0) 101.4) 10 94.4 95.9 94.4 98.4 99.5 95.499.5 99.1 (91.6-100.0) (93.9- (91.6- (94.4- (96.0- (90.4- (96.0- (93.2-100.5) 100.0) 101.0) 104.5) 97.8) 104.5) 102.4) 15 95.9 96.7 95.9 99.1100.9 96.8 100.9 100.2 (92.9-101.7) (94.9- (92.9- (95.1- (98.2- (92.7-(98.2- (95.2- 101.3) 101.7) 100.8) 105.3) 100.6) 105.3) 103.3) 30 98.498.3 98.4 99.8 102.4 98.1 102.4 101.7 (96.0-104.4) (95.7- (96.0- (96.5-(98.9- (95.0- (98.9- (97.4- 102.5) 104.4) 102.4) 104.9) 102.7) 104.9)104.3)

TABLE 5c Dissolution of selected SP TAB formulations. Mean Result (%dissolved) (Range shown in brackets) Time B7-5B-10-2 B7-9-10-2B6-5B-40-2 B6-5B-40-4 Point (min) Initial 6 months Initial 6 monthsInitial 6 months Initial 6 months 5 89.9 87.1 88.4 91.7 82.4 89.4 82.495.6 (84.0-95.1) (77.1- (74.3- (79.3- (68.8- (84.0- (68.8- (93.9- 96.5)100.0) 99.8) 92.1) 95.8) 92.1) 98.7) 10 92.5 91.3 93.9 97.1 92.6 91.292.6 98.1 (88.5-96.9) (84.7- (85.9- (93.7- (88.4- (87.9- (88.4- (96.2-98.9) 101.0) 101.8) 100.3) 96.5) 100.3) 101.4) 15 93.5 93.1 94.6 98.693.9 92.9 93.9 98.9 (90.0-98.0) (87.5- (88.6- (96.0- (89.4- (90.1-(89.4- (97.0- 99.6) 101.2) 102.6) 100.7) 98.1) 100.7) 102.3) 30 96.197.4 96.3 100.7 95.4 95.4 95.4 100.2 (93.7-100.4) (93.4- (92.4- (99.3-(91.5- 92.6- (91.5- (97.9- 101.1) 101.8) 103.8) 101.6) 99.7) 101.6)103.4)

TABLE 6 Lisinopril assay. Mean Result (% label claim) (Replicate resultsSample Time Point shown in brackets) A6a-9-40-1 Initial 98.9 (99.6,98.2) 6 months 96.2 (97.6, 94.8) A6a-9-40-3 Initial 98.9 (99.6, 98.2) 6months  98.8 (96.8, 100.7) A6a-5B-40-1 Initial 100.7 (102.7, 98.6) 6months 98.1 (98.1, 98.0) A6a-5B-40-3 Initial 100.7 (102.7, 98.6) 6months 99.2 (99.7, 98.6) B7-5B-10-2 Initial 97.9 (98.5, 97.2) 6 months98.6 (97.9, 99.3) B7-9-10-2 Initial  96.6 (93.1, 100.1)* 6 months 95.6(93.4, 97.8) B6-5B-40-2 Initial 96.6 (95.2, 97.9) 6 months 97.7 (97.3,98.1) B6-5B-40- 4 Initial 96.6 (95.2, 97.9) 6 months 98.3 (97.3, 99.2)

TABLE 7 Diketopiperazine (DKP) assay. DKP (%) (Replicate results SampleTime Point shown in brackets) A6a-9-40-1 Initial Not detected 6 months<0.05 (<0.05, <0.05) A6a-9-40-3 Initial Not detected 6 months <0.05(<0.05, <0.05) A6a-5B-40-1 Initial Not detected 6 months <0.05 (<0.05,<0.05) A6a-5B-40-3 Initial Not detected 6 months <0.05 (<0.05, <0.05)B7-5B-10-2 Initial Not detected 6 months 0.08 (0.08, 0.07) B7-9-10-2Initial Not detected 6 months 0.07 (0.07, 0.07) B6-5B-40-2 Initial Notdetected 6 months 0.06 (0.06, 0.06) B6-5B-40-4 Initial Not detected 6months 0.05 (0.05, 0.05)

TABLE 8a Formulations of Table 8b. Strength Desiccant ReferenceFormulation (mg lisinopril) Mass (g) A6a-10-2 A6a 10 2 A6a-40-3 40 3B6-10-2 B6 10 2 B6-40-3 40 3

TABLE 8b Dissolution of selected IEM TAB formulations. Mean Result (%dissolved) (Range shown in brackets) Time A6a-10-2 A6a-40-3 B6-10-2B6-40-3 Point (min) Initial 6 months Initial 6 months Initial 6 monthsInitial 6 months 5 48.3 58.3 39.1 49.3 76.5 84.3 76.7 84.4 (43.4-56.2)(52.1- (33.7- (42.5- (65.7- (80.1- (69.6- (72.7- 67.1) 46.5) 55.6) 86.7)95.4) 80.2) 89.9) 10 93.9 96.7 89.4 88.7 87.6 92.3 87.2 90.5 (91.1-97.1)(93.8- (74.9- (85.3- (81.7- (88.4- (80.3- (81.8- 101.9) 99.0) 92.8)90.1) 97.9) 93.2) 94.0) 15 98.1 101.4 98.6 93.4 89.2 94.5 91.2 93.1(97.2-100.1) (98.3- (86.9- (90.9- (84.3- (89.7- (84.0- (85.6- 105.9)106.8) 96.3) 93.1) 99.1) 96.4) 96.8) 30 97.8 103.1 102.5 96.2 92.5 96.994.9 95.3 (97.0-99.2) (100.6- (95.3- (93.2- (89.4- (92.2- (88.8- (89.8-106.4) 107.1) 98.3) 96.8) 100.6) 98.0) 98.9)

TABLE 9 Mean Result (% label claim) (Replicate Sample Time Point resultsshown in brackets) A6a-10-2 Initial  99.8 (98.7, 100.8) 6 months 97.7(96.4, 99.0) A6a-40-3 Initial  102.8 (102.2, 103.3) 6 months 96.8 (96.6,97.0) B6-10-2 Initial 93.3 (92.6, 93.9) 6 months 93.6 (93.8, 93.4)B6-40-3 Initial 100.1 (99.3, 100.8) 6 months 96.9 (97.3, 96.4)

TABLE 10 DKP (%) (Replicate results Sample Time Point shown in brackets)A6a-10-2 Initial Not detected 6 months 0.17 (0.18, 0.16) A6a-40-3Initial Not detected 6 months 0.18 (0.19, 0.17) B6-10-2 Initial Notdetected 6 months 0.28 (0.28, 0.28) B6-40-3 Initial Not detected 6months 0.24 (0.24, 0.24)

Example 12 Mechanical Stability Analysis

The mechanical stability of certain of the compositions provided hereinwas assessed when configured in an ingestible form (e.g., IEM-TAB,SP-TAB, or SP-CAP). Compositions comprising lisinopril in SP-TAB usingboth A6 and B6 blends pass ACF specifications out to at least 6 monthsat both 10 mg and 40 mg dose strength at all tested desiccation levels(e.g., 1-4 g desiccant) at 25° C./60% relative humidity (RH) packagedconditions (see FIG. 10 ); low percentage stochastic die fall-out (DFO)was observed at some time points (see FIG. 11 ). Compositions comprisinglisinopril in IEM-TAB using B6 blend passed ACF specifications out to atleast 6 months at both 10 mg and 40 mg dose strength at all testeddesiccation levels at 25° C./60% relative humidity (RH) packagedconditions, whereas A6 blend had multiple failures (see FIG. 12 ); B6blend also had substantially lower activation times than A6 blend, andthese activation times decline more steeply under accelerated conditions(i.e. 40° C./75% RH) (see FIG. 13 ). ACF stands for amplitude, count andfrequency. The ACF specification was set to ensure the signals from IEMwere received with a high degree of confidence. Amplitude corresponds tothe strength of the signal (data packet), count is the total number ofsuccessfully sent data packets, and frequency refers to the rate atwhich the data packets are being sent.

It is to be understood that this disclosure is not limited to particularembodiments described, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present disclosure will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the disclosure, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure,representative illustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present disclosure is not entitled to antedate suchpublication by virtue of prior disclosure. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing disclosure has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this disclosure that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

Accordingly, the preceding merely illustrates the principles of thedisclosure. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the disclosure andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the disclosure and theconcepts contributed by the inventors to furthering the art, and are tobe construed as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the disclosure as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure.

What is claimed is:
 1. An ingestible composition comprising: 1) about10% w/w lisinopril; about 15% w/w dicalcium phosphate, dihydrate; about53.85% w/w mannitol (50 um); about 10% w/w pregelatinized starch; OR 2)about 7.3% w/w lisinopril; about 30% w/w dicalcium phosphate, dihydrate;about 24.6% w/w mannitol (50 um); about 20% w/w pregelatinized starch;OR 3) about 10.21% w/w lisinopril; about 15.31% w/w dicalcium phosphate,dihydrate; about 58.02% w/w mannitol (180 um); about 15.31% w/wpregelatinized starch; OR 4) about 9.69% w/w lisinopril; about 14.53%w/w dicalcium phosphate, dihydrate; about 55.09% w/w mannitol (180 um);about 14.53% w/w pregelatinized starch; OR 5) about 9.18% w/wlisinopril; about 13.76% w/w dicalcium phosphate, dihydrate; about52.16% w/w mannitol (180 um); about 13.76% w/w pregelatinized starch; OR6) about 18.18% w/w lisinopril; about 1318% w/w dicalcium phosphate,dihydrate; about 47.59% w/w mannitol (50 um); about 10% w/wpregelatinized starch; OR 7) about 18.18% w/w lisinopril; about 14.32%w/w dicalcium phosphate, dihydrate; about 51.36% w/w mannitol (50 um);about 5% w/w pregelatinized starch; OR 8) about 7.27% w/w lisinopril;about 30% w/w dicalcium phosphate, dihydrate; about 24.58% w/w mannitol(50 um); about 20% w/w pregelatinized starch; OR 9) about 10% w/wlisinopril; about 28% w/w dicalcium phosphate, dihydrate; about 22.85%w/w mannitol (50 um); about 20% w/w pregelatinized starch; OR 10) about10.26% w/w lisinopril; about 15.38% w/w dicalcium phosphate, dihydrate;about 58.32% w/w mannitol (180 um); about 15.38% w/w pregelatinizedstarch; OR 11) about 10.16% w/w lisinopril; about 15.23% w/w dicalciumphosphate, dihydrate; about 57.73% w/w mannitol (180 um); about 15.23%w/w pregelatinized starch; OR 12) about 10.05% w/w lisinopril; about15.07% w/w dicalcium phosphate, dihydrate; about 57.14% w/w mannitol(180 um); about 15.07% w/w pregelatinized starch; OR 13) about 10.1% w/wlisinopril; about 15.15% w/w dicalcium phosphate, dihydrate; about57.44% w/w mannitol (180 um); about 15.15% w/w pregelatinized starch; OR14) about 10% w/w lisinopril; about 15% w/w dicalcium phosphate,dihydrate; about 56.85% w/w mannitol (180 um); about 15% w/wpregelatinized starch; OR 15) about 9.74% w/w lisinopril; about 14.61%w/w dicalcium phosphate, dihydrate; about 55.39% w/w mannitol (180 um);about 14.61% w/w pregelatinized starch; OR 16) about 10.62% w/wlisinopril; about 15.92% w/w dicalcium phosphate, dihydrate; about57.18% w/w mannitol (180 um); about 10.62% w/w pregelatinized starch; OR17) about 10.06% w/w lisinopril; about 15.08% w/w dicalcium phosphate,dihydrate; about 54.16% w/w mannitol (180 um); about 10.06% w/wpregelatinized starch; and an ingestible identifier comprising: anintegrated circuit comprising silicon, aluminum, silicon dioxide, andsilicon nitride; a wafer comprising titanium, titanium-tungsten, gold,magnesium, copper (I) chloride, and hydroxypropyl cellulose; and a skirtfilm comprising ethyl cellulose, hydroxypropyl cellulose, and triethylcitrate.
 2. The ingestible composition of claim 1, wherein theingestible composition further comprises iron oxide yellow or water, orboth.
 3. The ingestible composition of claim 1, wherein the ingestiblecomposition comprises about 0.10% to about 0.20% w/w iron oxide yellow.4. The ingestible composition of claim 1, wherein the ingestiblecomposition comprises about 0.10% to about 0.15% w/w iron oxide yellow.5. The ingestible composition of claim 1, wherein the ingestiblecomposition comprises about 0.15% to about 0.20% w/w iron oxide yellow.6. The ingestible composition of claim 1, wherein the ingestiblecomposition comprises about 0.15% w/w iron oxide yellow.
 7. Theingestible composition of claim 1, wherein the ingestible compositioncomprises: about 0% to about 30.0% w/w microcrystalline cellulose; about0% to about 2.5% w/w croscarmellose sodium; about 0% to about 0.20% w/wiron oxide; and about 0% to about 0.30% w/w FD&C yellow #6.
 8. Theingestible composition of claim 7, wherein the comprises about 0 or 16%w/w microcrystalline cellulose.
 9. The ingestible composition of claim8, wherein the ingestible composition comprises about 0 or 2% w/wcroscarmellose sodium.
 10. The ingestible composition of claim 9,wherein the ingestible composition comprises about 0.14 or 0.15% w/wiron oxide.
 11. The ingestible composition of claim 10, wherein theingestible composition comprises about 0% w/w FD&C yellow #6.